BioPAX pathway converted from "Deubiquitination" in the Reactome database.

Deubiquitination

Ubiquitination, the modification of proteins by the covalent attachment of ubiquitin (Ub), is a key regulatory mechanism for many many cellular processes, including protein degradation by the 26S proteasome. Ub conjugates linked via lysine 48 (K48) target substrates to the proteasome, whereas those linked via any of the six other Ub lysines can alter the function of the modified protein without leading to degradation. Deubiquitination, the reversal of this modification, regulates the function of ubiquitin-conjugated proteins. Deubiquitinating enzymes (DUBs) catalyze the removal of Ub and regulate Ub-mediated pathways. Given that Ub is covalently-linked to proteins destined to be degraded, it is a surprisingly long-lived protein in vivo (Haas & Bright 1987). This is due to the removal of Ub from its conjugates by DUBs prior to proteolysis. This may represent a quality control mechanism that prevents the degradation of proteins that were inappropriately tagged for degradation (Lam et al. 1997). DUBs are responsible for processing inactive Ub precursors and for keeping the 26S proteasome free of unanchored Ub chains that compete for Ub-binding sites. DUBs can be grouped into five families based on their conserved catalytic domains (Amerik & Hochstrasser 2004). Four of these families are thiol proteases and comprise the bulk of DUBs, while the fifth family is a small group of Ub specific metalloproteases. Thiol protease DUBs contain a Cys-His-Asp/Asn catalytic triad in which the Asp/Asn functions to polarize and orient the His, while the His serves as a general acid/base by both priming the catalytic Cys for nucleophilic attack on the (iso)peptide carbonyl carbon and by donating a proton to the lysine epsilon-amino leaving group. The nucleophilic attack of the catalytic Cys on the carbonyl carbon produces a negatively charged transition state that is stabilized by an oxyanion hole composed of hydrogen bond donors. A Cys-carbonyl acyl intermediate ensues and is then hydrolyzed by nucleophilic attack of a water molecule to liberate a protein C-terminal carboxylate and regenerate the enzyme. Ub binding often causes structural rearrangements necessary for catalysis. Many DUBs are inactivated by oxidation of the catalytic cysteine to sulphenic acid (single bond SOH) (Cotto-Rios et al. 2012, Lee et al. 2013). This can be reversed by reduction with DTT or glutathione. The sulphenic acid can be irreversibly oxidized to sulphinic acid (single bond SO2H) or sulphonic acid (single bond SO3H). Thiol proteases are reversibly inhibited by Ub C-terminal aldehyde, forming a thio-hemiacetal between the aldehyde group and the active site thiol.

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

UCH proteinases

DUBs of the Ub C-terminal Hydrolase (UCH) family are thiol proteases that have an N-terminal catalytic domain sometimes followed by C-terminal extensions that mediate protein-protein interactions. Humans have four UCH DUBs (UCH-L1, UCH-L3, UCH37/UCH-L5, and BAP1) that can be divided into the smaller UCH DUBs (UCH-L1 and UCH-L3), which cleave small leaving groups from the C-terminus of ubiquitin (Larsen et al. 1998), and the larger UCH DUBs (UCH37 and BAP1), which can disassemble poly-Ub chains (Misaghi et al. 2009, Lam et al. 1997).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

ADRM1 binds 26S proteasome

ADRM1 (also called Rpn13) interacts with the 26S proteasome base unit PRDM1 (Rpn2) via its amino-terminus and is found in the majority of 26S proteasomes. It is a receptor for Ubiquitin (Ub) that can bind K48-linked di-Ub (Schreiner et al. 2008, Husnjak et al. 2008) and de-ubiquitinating enzymes (DUBs) such as PSMD14 (Rpn11, POH1), USP14, and UCHL5 (UCH37) (Reyes-Turcu et al., 2009). Together, these DUBs disassemble poly-Ub chains and recycle ubiquitin during proteasomal degradation.

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 68819

cytosolGO000582926S proteasome [cytosol]

26S proteasome

Reactome DB_ID: 68788

UniProt:O75832 PSMD10

PSMD10

PSMD10FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD10:PSMC4:PSMC5:PAAF1 module which probably assembles with a PSMD5:PSMC2:PSMC1:PSMD2 module. Independently of the proteasome, regulates EGF-induced AKT activation through inhibition of the RHOA/ROCK/PTEN pathway, leading to prolonged AKT activation. Plays an important role in RAS-induced tumorigenesis.FUNCTION Acts as an proto-oncoprotein by being involved in negative regulation of tumor suppressors RB1 and p53/TP53. Overexpression is leading to phosphorylation of RB1 and proteasomal degradation of RB1. Regulates CDK4-mediated phosphorylation of RB1 by competing with CDKN2A for binding with CDK4. Facilitates binding of MDM2 to p53/TP53 and the mono- and polyubiquitination of p53/TP53 by MDM2 suggesting a function in targeting the TP53:MDM2 complex to the 26S proteasome. Involved in p53-independent apoptosis. Involved in regulation of NF-kappa-B by retaining it in the cytoplasm. Binds to the NF-kappa-B component RELA and accelerates its XPO1/CRM1-mediated nuclear export.SUBUNIT Part of transient complex containing PSMD10, PSMC4, PSMC5 and PAAF1 formed during the assembly of the 26S proteasome. Stays associated throughout the assembly of the PA700/19S RC and is released upon association with the 20S core. Interacts with PSMC4. Interacts with RB1. Interacts with CDK4. Interacts with MDM2. Interacts with RELA. Associates with a CDK4:CCND2 serine/threonine kinase complex. Interacts with ARHGDIA and increases the interaction between ARHGDIA and RHOA, hence promotes ARHGDIA inactivation of RHOA and ROCK.TISSUE SPECIFICITY Tends to be up-regulated in cancer cells with RAS mutations, including lung cancers and adenocarconimas (at protein level).CAUTION Was initially identified as a genuine component of the 26S proteasome.

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtO75832

Chain Coordinates

EQUAL

226

EQUAL

Reactome DB_ID: 68796

UniProt:Q13200 PSMD2

PSMD2

TRAP2PSMD2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.FUNCTION Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD2 (PubMed:27428775, PubMed:27342858). Interacts with RPGRIP1L (By similarity). Interacts with CRY1 in a KDM8-dependent manner (By similarity).TISSUE SPECIFICITY Found in skeletal muscle, liver, heart, brain, kidney, pancreas, lung and placenta.SIMILARITY Belongs to the proteasome subunit S2 family.

UniProtQ13200

EQUAL

908

EQUAL

Reactome DB_ID: 68800

UniProt:P55036 PSMD4

PSMD4

MCB1PSMD4FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMD4 acts as an ubiquitin receptor subunit through ubiquitin-interacting motifs and selects ubiquitin-conjugates for destruction. Displays a preferred selectivity for longer polyubiquitin chains.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD4 (PubMed:27428775, PubMed:27342858). Interacts with NUB1 (PubMed:11585840). Interacts with SQSTM1 (PubMed:15340068). Interacts with UBQLN4 (PubMed:15280365). Interacts with UBE3A (PubMed:22645313). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with DDI2 (PubMed:29290612).DOMAIN The 2 UIM motifs are involved in the binding to a multi-ubiquitin chain in a cooperative way.SIMILARITY Belongs to the proteasome subunit S5A family.

UniProtP55036

EQUAL

377

EQUAL

Reactome DB_ID: 68792

UniProt:O00232 PSMD12

PSMD12

PSMD12FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex (PubMed:27428775,PubMed:27342858). The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775,PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits including PSMD12, a base containing 6 ATPases and few additional components (PubMed:27428775,PubMed:27342858). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit p55 family.

UniProtO00232

EQUAL

456

EQUAL

Reactome DB_ID: 68762

UniProt:P28062 PSMB8

PSMB8

PSMB5iRING10Y2LMP7PSMB8FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. Involved in the generation of spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (PubMed:27049119). Acts as a major component of interferon gamma-induced sensitivity. Plays a key role in apoptosis via the degradation of the apoptotic inhibitor MCL1. May be involved in the inflammatory response pathway. In cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1) results in immunoproteasome deficiency. Required for the differentiation of preadipocytes into adipocytes.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB5. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Directly interacts with POMP. Interacts with TAP1.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma and IRF1 (at protein level). Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Down-regulated by the selective inhibitor PR-957. Down-regulated in mature dendritic cells by HSV-1 infection. Up-regulated by heat shock treatment.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family.

UniProtP28062

EQUAL

276

EQUAL

Reactome DB_ID: 68790

UniProt:O00231 PSMD11

PSMD11

PSMD11FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. In the complex, PSMD11 is required for proteasome assembly. Plays a key role in increased proteasome activity in embryonic stem cells (ESCs): its high expression in ESCs promotes enhanced assembly of the 26S proteasome, followed by higher proteasome activity.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD11, a base containing 6 ATPases and few additional components.TISSUE SPECIFICITY Highly expressed in embryonic stem cells (ESCs). Expression decreases as ESCs differentiate.INDUCTION By FOXO4; expression in embryonic stem cells (ESCs) is mediated by FOXO4.PTM Phosphorylated by AMPK.SIMILARITY Belongs to the proteasome subunit S9 family.

UniProtO00231

EQUAL

422

EQUAL

Reactome DB_ID: 68802

UniProt:Q16401 PSMD5

PSMD5

PSMD5KIAA0072FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD5:PSMC2:PSMC1:PSMD2 module which probably assembles with a PSMD10:PSMC4:PSMC5:PAAF1 module followed by dissociation of PSMD5.SUBUNIT Interacts with PSMC1, PSMC2, PSMD1 and PSMD6. Part of transient complex containing PSMD5, PSMC2, PSMC1 and PSMD2 formed during the assembly of the 26S proteasome.DOMAIN Rich in dileucine repeats, which have been implicated in trafficking of a variety of transmembrane proteins.SIMILARITY Belongs to the proteasome subunit S5B/HSM3 family.CAUTION Was initially identified as a genuine component of the 26S proteasome.

UniProtQ16401

EQUAL

504

EQUAL

Reactome DB_ID: 68808

UniProt:P48556 PSMD8

PSMD8

PSMD8FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD8, a base containing 6 ATPases and few additional components. Interacts with DDI2 (PubMed:29290612). Interacts with TASOR (By similarity).SIMILARITY Belongs to the proteasome subunit S14 family.CAUTION It is uncertain whether Met-1 or Met-64 is the initiator.

UniProtP48556

EQUAL

350

EQUAL

Reactome DB_ID: 68744

UniProt:P49721 PSMB2

PSMB2

PSMB2FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Up-regulated in ovarian cancer cell lines.SIMILARITY Belongs to the peptidase T1B family.

UniProtP49721

EQUAL

201

EQUAL

Reactome DB_ID: 68810

UniProt:O00233 PSMD9

PSMD9

PSMD9FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). During the base subcomplex assembly is part of an intermediate PSMD9:PSMC6:PSMC3 module, also known as modulator trimer complex; PSMD9 is released during the further base assembly process.SUBUNIT Interacts with PSMC3. Part of a transient complex (modulator) containing PSMD9, PSMC6 and PSMC3 formed during the assembly of the 26S proteasome.TISSUE SPECIFICITY Expressed in all tissues tested, highly expressed in liver and kidney.SIMILARITY Belongs to the proteasome subunit p27 family.CAUTION Was initially identified as a component of the 26S proteasome.

UniProtO00233

EQUAL

223

EQUAL

Reactome DB_ID: 68786

UniProt:Q99460 PSMD1

PSMD1

PSMD1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD1 (PubMed:27428775, PubMed:27342858). Interacts with ADRM1 (PubMed:16990800, PubMed:16906146). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the proteasome subunit S1 family.

UniProtQ99460

EQUAL

953

EQUAL

Reactome DB_ID: 68734

UniProt:P60900 PSMA6

PSMA6

PSMA6PROS27FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with ALKBH4 (PubMed:23145062).SIMILARITY Belongs to the peptidase T1A family.

UniProtP60900

EQUAL

246

EQUAL

Reactome DB_ID: 68777

UniProt:P43686 PSMC4

PSMC4

TBP7PSMC4MIP224FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC4 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC4 and few additional components (PubMed:27428775,PubMed:27342858). Interacts with NR1I3. Interacts with PAAF1 (PubMed:15831487). Interacts with TRIM5 (PubMed:22078707). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the AAA ATPase family.

UniProtP43686

EQUAL

418

EQUAL

Reactome DB_ID: 68814

UniProt:Q9UL46 PSME2

PSME2

PSME2FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family.

UniProtQ9UL46

EQUAL

239

EQUAL

Reactome DB_ID: 68818

UniProt:Q92530 PSMF1

PSMF1

PSMF1FUNCTION Plays an important role in control of proteasome function. Inhibits the hydrolysis of protein and peptide substrates by the 20S proteasome. Also inhibits the activation of the proteasome by the proteasome regulatory proteins PA700 and PA28.SUBUNIT Monomer and homodimer. Interacts with FBXO7. Interacts with the 20S proteasome.SIMILARITY Belongs to the proteasome inhibitor PI31 family.

UniProtQ92530

EQUAL

271

EQUAL

Reactome DB_ID: 68753

UniProt:P28074 PSMB5

PSMB5

PSMB5XLMPXMB1FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB5 displays a chymotrypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Directly interacts with POMP (PubMed:15944226). Interacts with ABCB1 and TAP1 (PubMed:15488952).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Induced in breast cancer tissue. Up-regulated by sulforaphane in breast cancer cells.SIMILARITY Belongs to the peptidase T1B family.

UniProtP28074

EQUAL

263

EQUAL

Reactome DB_ID: 68765

UniProt:P28065 PSMB9

PSMB9

LMP2PSMB6iRING12PSMB9FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB6 by PSMB9 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB6. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Up-regulated by tumor necrosis factor-alpha (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by heat shock treatment. Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.MISCELLANEOUS Encoded in the MHC class II region.MISCELLANEOUS A model for self-activation in which residue Thr-21 serves as nucleophile and Lys-53 as proton donor/acceptor has been proposed. Subunit processing of mammalian beta-subunits proceeds via a novel ordered two-step mechanism involving autocatalysis.SIMILARITY Belongs to the peptidase T1B family.

UniProtP28065

EQUAL

219

EQUAL

Reactome DB_ID: 947607

UniProt:A5LHX3 PSMB11

PSMB11

PSMB11FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Incorporated instead of PSMB5 or PSMB8, this unit reduces the chymotrypsin-like activity of the proteasome (By similarity). Plays a pivotal role in development of CD8-positive T cells (By similarity).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Incorporated instead of PSMB5 and PSMB8.SIMILARITY Belongs to the peptidase T1B family.

UniProtA5LHX3

EQUAL

300

EQUAL

Reactome DB_ID: 68798

UniProt:O43242 PSMD3

PSMD3

PSMD3FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD3, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit S3 family.

UniProtO43242

EQUAL

534

EQUAL

Reactome DB_ID: 8866674

UniProt:P60896 SEM1

SEM1

SEM1C7orf76SHFDG1SHFM1DSS1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:15117943). Component of the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and thus transcription-associated genomic instability. R-loop accumulation increases in SEM1-depleted cells.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including SEM1, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Belongs to the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). Interacts with the C-terminal of BRCA2 (PubMed:10373512, PubMed:21719596).TISSUE SPECIFICITY Expressed in limb bud, craniofacial primordia and skin.SIMILARITY Belongs to the DSS1/SEM1 family.

UniProtP60896

EQUAL

Reactome DB_ID: 68750

UniProt:P28070 PSMB4

PSMB4

PSMB4PROS26FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Interacts with PRPF19 (PubMed:11571290, PubMed:12097147).SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax protein.SUBUNIT (Microbial infection) Interacts with HIV-1 Nef and Tat proteins.INDUCTION Up-regulated in fibrolamellar carcinomas.SIMILARITY Belongs to the peptidase T1B family.CAUTION A report observed N-glycosylation at Asn-83 (PubMed:19139490). However, as the protein does not localize in an extracellular compartment of the cell, additional evidence is required to confirm this result.

UniProtP28070

EQUAL

264

EQUAL

Reactome DB_ID: 68732

UniProt:P28066 PSMA5

PSMA5

PSMA5FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA5 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly.TISSUE SPECIFICITY Expressed in fetal brain (at protein level).INDUCTION Up-regulated in colon cancer cell lines. Up-regulated in fetal Down syndrome (DS) brain (at protein level). May be the target of the transcriptional activator NFE2L2.SIMILARITY Belongs to the peptidase T1A family.

UniProtP28066

EQUAL

241

EQUAL

Reactome DB_ID: 68738

UniProt:P20618 PSMB1

PSMB1

PSC5PSMB1FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with SERPINB2. Interacts with RFPL4A (By similarity).SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.SIMILARITY Belongs to the peptidase T1B family.

UniProtP20618

EQUAL

241

EQUAL

Reactome DB_ID: 68774

UniProt:P17980 PSMC3

PSMC3

PSMC3TBP1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC3 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC3 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.PTM Sumoylated by UBE2I in response to MEKK1-mediated stimuli.SIMILARITY Belongs to the AAA ATPase family.

UniProtP17980

EQUAL

439

EQUAL

Reactome DB_ID: 947606

UniProt:Q14997 PSME4

PSME4

PSME4KIAA0077FUNCTION Associated component of the proteasome that specifically recognizes acetylated histones and promotes ATP- and ubiquitin-independent degradation of core histones during spermatogenesis and DNA damage response. Recognizes and binds acetylated histones via its bromodomain-like (BRDL) region and activates the proteasome by opening the gated channel for substrate entry. Binds to the core proteasome via its C-terminus, which occupies the same binding sites as the proteasomal ATPases, opening the closed structure of the proteasome via an active gating mechanism. Component of the spermatoproteasome, a form of the proteasome specifically found in testis: binds to acetylated histones and promotes degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. Also involved in DNA damage response in somatic cells, by promoting degradation of histones following DNA double-strand breaks.SUBUNIT Homodimer. Interacts with the 20S and 26S proteasomes. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.DOMAIN The bromodomain-like (BRDL) region specifically recognizes and binds acetylated histones.SIMILARITY Belongs to the BLM10 family.

UniProtQ14997

EQUAL

1843

EQUAL

Reactome DB_ID: 68783

UniProt:P62333 PSMC6

PSMC6

PSMC6SUG2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC6 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC6 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family.CAUTION Alternative initiation from an upstream conserved methionine cannot be fully excluded but is not experimentally supported while initiation from the displayed methionine is supported by PubMed:17323924.

UniProtP62333

EQUAL

389

EQUAL

Reactome DB_ID: 68759

UniProt:Q99436 PSMB7

PSMB7

PSMB7ZFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB7 displays a trypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.TISSUE SPECIFICITY Expressed at a low level in colonic mucosa. Up-regulated in colorectal cancer tissues.SIMILARITY Belongs to the peptidase T1B family.

UniProtQ99436

EQUAL

277

EQUAL

Reactome DB_ID: 68747

UniProt:P49720 PSMB3

PSMB3

PSMB3FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Up-regulated in asthenozoospermic sperm.SIMILARITY Belongs to the peptidase T1B family.

UniProtP49720

EQUAL

205

EQUAL

Reactome DB_ID: 68780

UniProt:P62195 PSMC5

PSMC5

PSMC5SUG1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC5 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC5 and few additional components (PubMed:27428775, PubMed:27342858). Component of a complex with USP49 and RUVBL1 (PubMed:23824326). Interacts with PRPF19. Interacts with TRIM5 (PubMed:22078707). Interacts with NDC80 (PubMed:9295362, PubMed:10409732). Interacts with PAAF1 (PubMed:15831487). Interacts, in vitro, with the thyroid hormone receptor (in a thyroid hormone T3-dependent manner) and with retinoid X receptor (RXR) (By similarity). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the AAA ATPase family.

UniProtP62195

EQUAL

406

EQUAL

Reactome DB_ID: 68756

UniProt:P28072 PSMB6

PSMB6

PSMB6LMPYYFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB6 displays a peptidylglutamyl-hydrolizing activity also termed postacidic or caspase-like activity, meaning that the peptides bond hydrolysis occurs directly after acidic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Up-regulated in anaplastic thyroid cancer cell lines.SIMILARITY Belongs to the peptidase T1B family.

UniProtP28072

EQUAL

239

EQUAL

Reactome DB_ID: 68804

UniProt:Q15008 PSMD6

PSMD6

PSMD6KIAA0107PFAAP4FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD6, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S10 family.

UniProtQ15008

EQUAL

389

EQUAL

Reactome DB_ID: 68806

UniProt:P51665 PSMD7

PSMD7

MOV34LPSMD7FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD7, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD7 interacts with subunit PSMD4 through their respective MPN domain. Interacts with TRIM5 (PubMed:22078707).MISCELLANEOUS Does not bind a metal ion.SIMILARITY Belongs to the peptidase M67A family.

UniProtP51665

EQUAL

324

EQUAL

Reactome DB_ID: 68730

UniProt:P25789 PSMA4

PSMA4

PSMA4PSC9HC9FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interaction with HTLV-1 TAX protein favors NFKB1 activation.INDUCTION Down-regulated by antioxidants BO-653 and probucol.SIMILARITY Belongs to the peptidase T1A family.

UniProtP25789

EQUAL

261

EQUAL

Reactome DB_ID: 947610

UniProt:Q8TAA3 PSMA8

PSMA8

PSMA7LPSMA8FUNCTION Component of the spermatoproteasome, a proteasome specifically found in testis that promotes acetylation-dependent degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. The proteasome is a protein complexe that degrades unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Required for 20S core proteasome assembly, essential for the degradation of meiotic proteins RAD51 and RPA1 at late prophase I and the progression of meiosis I during spermatogenesis. Localizes to the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I.SUBUNIT Component of the outer alpha-ring of the 20S proteasome core which is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The catalytic chamber with the active sites is on the inside of the barrel. Interacts with canonical subunits of the spermatoproteasome, including proteasome activators PSME4 (also called PA200) and PSME3 (also called PA28-gamma). Interacts with proteasome-interacting proteins chaperones, ubiquitin ligases and ubiquitin specific proteases. Interacts with meiotic proteins cyclin dependent kinase CDK1 and the ATPase TRIP13 as well as proteins of the synaptonemal complex SIX6OS1 and SYCE3.SIMILARITY Belongs to the peptidase T1A family.

UniProtQ8TAA3

EQUAL

256

EQUAL

Reactome DB_ID: 68724

UniProt:P25786 PSMA1

PSMA1

PSMA1HC2NUPSC2PROS30FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with NOTCH3. Interacts with ZFAND1 (PubMed:29804830).INDUCTION Induced in breast cancer tissue (at protein level). Up-regulated in liver tumor tissues.SIMILARITY Belongs to the peptidase T1A family.

UniProtP25786

EQUAL

263

EQUAL

Reactome DB_ID: 68812

UniProt:Q06323 PSME1

PSME1

PSME1IFI5111FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring. PSME1 can form homoheptamers.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family.

UniProtQ06323

EQUAL

249

EQUAL

Reactome DB_ID: 68722

UniProt:O00487 PSMD14

PSMD14

PSMD14POH1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD4, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD4 interacts with subunit PSMD7 through their respective MPN domain. Interacts with TXNL1 (PubMed:19349277).TISSUE SPECIFICITY Widely expressed. Highest levels in heart and skeletal muscle.SIMILARITY Belongs to the peptidase M67A family. PSMD14 subfamily.

UniProtO00487

EQUAL

310

EQUAL

Reactome DB_ID: 68728

UniProt:P25788 PSMA3

PSMA3

PSMA3HC8PSC8FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with AURKB. Interacts with CDKN1A (PubMed:11350925). Interacts with MDM2 and RB1 (PubMed:16337594). Interacts with the C-terminus of TBXA2R isoform 2 (PubMed:17499743). Interacts with DNAJB2 (PubMed:15936278).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.SUBUNIT (Microbial infection) Interacts with hepatitis C virus (HCV) F protein.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA3 proteins.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Up-regulated by bacterial lipopolysaccharides (LPS) and TNF.SIMILARITY Belongs to the peptidase T1A family.

UniProtP25788

EQUAL

255

EQUAL

Reactome DB_ID: 68736

UniProt:O14818 PSMA7

PSMA7

PSMA7HSPCFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA7 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (PubMed:16251969). Interacts with HIF1A. Interacts with RAB7A (PubMed:14998988). Interacts with PRKN (PubMed:15987638). Interacts with ABL1 and ABL2 (PubMed:16678104). Interacts with EMAP2 (PubMed:19362550). Interacts with MAVS (PubMed:19734229).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.SUBUNIT (Microbial infection) Interacts with hepatitis B virus X protein (HBX).INDUCTION Down-regulated by the ribozyme Rz3'X. Up-regulated in colorectal cancer tissues.PTM Phosphorylation by ABL1 or ABL2 leads to an inhibition of proteasomal activity and cell cycle transition blocks.SIMILARITY Belongs to the peptidase T1A family.

UniProtO14818

EQUAL

248

EQUAL

Reactome DB_ID: 68816

UniProt:P61289 PSME3

PSME3

PSME3FUNCTION Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits. Facilitates the MDM2-p53/TP53 interaction which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53/TP53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. May also be involved in cell cycle regulation. Mediates CCAR2 and CHEK2-dependent SIRT1 inhibition (PubMed:25361978).SUBUNIT Homoheptamer; the stability of the heptamer is essential for the specific activation of the trypsine-like subunit and inhibition of the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits of the proteasome. Interacts with p53/TP53 and MDM2. Interacts with MAP3K3 (By similarity). Associates with the proteasome. Interacts with CCAR2. Interacts with PSME3IP1 (via C-terminus); the interaction is direct and promotes the association of PSME3 with the 20S proteasome (PubMed:29934401). Interacts with COIL; the interaction is inhibited by PSME3IP1 (PubMed:29934401).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus UL27.INDUCTION Up-regulated in thyroid carcinoma cells.DOMAIN The C-terminal sequences affect heptamer stability and proteasome affinity.PTM Phosphorylated by MAP3K3 (By similarity). Phosphorylation at Ser-247 promotes its association with CCAR2.PTM Acetylation at the major site Lys-195 is important for oligomerization and ability to degrade its target substrates. Deacetylated by SIRT1.SIMILARITY Belongs to the PA28 family.

UniProtP61289

EQUAL

254

EQUAL

Reactome DB_ID: 68771

UniProt:P35998 PSMC2

PSMC2

MSS1PSMC2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC2 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with NDC80/HEC; this interaction is detected only during M phase. Interacts and SQSTM1 (PubMed:15340068). Interacts with PAAF1 (PubMed:15831487). Directly interacts with TRIM5 (PubMed:22078707).INDUCTION Expression is not cell cycle-dependent and occurs throughout the cell cycle.SIMILARITY Belongs to the AAA ATPase family.

UniProtP35998

EQUAL

433

EQUAL

Reactome DB_ID: 68726

UniProt:P25787 PSMA2

PSMA2

PSMA2PSC3HC3FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Down-regulated in response to enterovirus 71 (EV71) infection (at protein level).PTM Phosphorylated on tyrosine residues; which may be important for nuclear import.SIMILARITY Belongs to the peptidase T1A family.

UniProtP25787

EQUAL

234

EQUAL

Reactome DB_ID: 68768

UniProt:P62191 PSMC1

PSMC1

PSMC1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC1 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC1 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with SCA7 (PubMed:11734547). Interacts with NGLY1 (PubMed:15358861). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family.

UniProtP62191

EQUAL

440

EQUAL

Reactome DB_ID: 68741

UniProt:P40306 PSMB10

PSMB10

LMP10MECL1PSMB10FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB7. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma (at protein level). Up-regulated by IRF1. Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family.

UniProtP40306

EQUAL

273

EQUAL

Reactome DB_ID: 68794

UniProt:Q9UNM6 PSMD13

PSMD13

PSMD13FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD13, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S11 family.

UniProtQ9UNM6

EQUAL

376

EQUAL

Reactome Database ID Release 7568819Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68819ReactomeR-HSA-68819

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68819.2

Reactome DB_ID: 5665939

UniProt:Q16186 ADRM1

ADRM1

ADRM1GP110FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. Within the complex, functions as a proteasomal ubiquitin receptor. Engages and activates 19S-associated deubiquitinases UCHL5 and PSMD14 during protein degradation. UCHL5 reversibly associate with the 19S regulatory particle whereas PSMD14 is an intrinsic subunit of the proteasome lid subcomplex.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:16990800). Interacts with the proteasomal scaffolding protein PSMD1 (PubMed:16990800,PubMed:16815440, PubMed:16906146, PubMed:20471946). Interacts with deubiquitinase UCHL5; this interaction activates the auto-inhibited UCHL5 by deoligomerizing it (PubMed:17139257, PubMed:24752541, PubMed:25702870, PubMed:25702872). Interacts with UBQLN2 and ubiquitin (PubMed:27396824).DOMAIN The Pru (pleckstrin-like receptor for ubiquitin) domain mediates interactions with PSMD1 and ubiquitin. Preferential binding to the proximal subunit of K48-linked diubiquitin allows UCHL5 access to the distal subunit.SIMILARITY Belongs to the ADRM1 family.CAUTION Although initially described as a cell membrane glycoprotein, ADRM1 is intracellular and non-glycosylated, and has probably no direct role in cell adhesion.

UniProtQ16186

EQUAL

407

EQUAL

Reactome DB_ID: 5665858

ADRM1:26S proteasome [cytosol]

ADRM1:26S proteasome

Reactome DB_ID: 68819

Reactome DB_ID: 5665939

EQUAL

407

EQUAL

Reactome Database ID Release 755665858Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665858ReactomeR-HSA-5665858

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665858.2Reactome Database ID Release 755665871Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665871ReactomeR-HSA-5665871

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665871.218497817Pubmed2008Proteasome subunit Rpn13 is a novel ubiquitin receptorHusnjak, KoraljkaElsasser, SuzanneZhang, NaixiaChen, XiangRandles, LeahShi, YuanHofmann, KayWalters, Kylie JFinley, DanielDikic, IvanNature 453:481-818497827Pubmed2008Ubiquitin docking at the proteasome through a novel pleckstrin-homology domain interactionSchreiner, PatrickChen, XiangHusnjak, KoraljkaRandles, LeahZhang, NaixiaElsasser, SuzanneFinley, DanielDikic, IvanWalters, Kylie JGroll, MichaelNature 453:548-5219489724Pubmed2009Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymesReyes-Turcu, Francisca EVentii, Karen HWilkinson, Keith DAnnu. Rev. Biochem. 78:363-97

ADRM1:26S proteaseome binds UCHL5

The C-terminal extension of UCHL5 (UCH37) binds to ADRM1, part of the proteasomal 19S regulatory subunit which is itself a subunit of the 26S proteasome. Binding of UCHL5 enhances its DUB activity (Qiu et al. 2006). UCHL5 forms oligomers in solution that have very low DUB activity. Binding with ADRM1 is 1:1, preventing oligomerization of UCHL5 while making the active site of UCHL5 accessible to Ubiquitin (Jiao et al. 2014). When associated with the proteasome, UCHL5 disassembles poly-Ub chains by hydrolyzing the distal ubiquitin from a chain. This dissassembly of the degradation signal from only the distal end of polyubiquitin chains may selectively rescue poorly ubiquitinated or slowly degraded Ub-protein conjugates from proteolysis (Lam et al. 1997).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 1629778

UniProt:Q9Y5K5 UCHL5

UCHL5

AD-019UCH37UCHL5CGI-70FUNCTION Protease that specifically cleaves 'Lys-48'-linked polyubiquitin chains. Deubiquitinating enzyme associated with the 19S regulatory subunit of the 26S proteasome. Putative regulatory component of the INO80 complex; however is inactive in the INO80 complex and is activated by a transient interaction of the INO80 complex with the proteasome via ADRM1.ACTIVITY REGULATION Activated by ADRM1. Inhibited by interaction with NFRKB.SUBUNIT Component of the 19S (PA700) regulatory complex of the 26S proteasome. Interacts with ADRM1 and NFRKB; in vitro ADRM1 and NFRKB compete for interaction with UCHL5. Component of the INO80 complex; specifically part of a complex module associated with N-terminus of INO80.SIMILARITY Belongs to the peptidase C12 family.

UniProtQ9Y5K5

EQUAL

329

EQUAL

Reactome DB_ID: 5665858

Reactome DB_ID: 5665845

ADRM1:26S proteasome:UCHL5 [cytosol]

ADRM1:26S proteasome:UCHL5

Reactome DB_ID: 1629778

EQUAL

329

EQUAL

Reactome DB_ID: 5665858

Reactome Database ID Release 755665845Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665845ReactomeR-HSA-5665845

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665845.2Reactome Database ID Release 755665854Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665854ReactomeR-HSA-5665854

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665854.217139257Pubmed2006hRpn13/ADRM1/GP110 is a novel proteasome subunit that binds the deubiquitinating enzyme, UCH37Qiu, XBOuyang, Song-YingLi, Chao-JunMiao, ShiyingWang, LinfangGoldberg, Alfred LEMBO J. 25:5742-5316990800Pubmed2006A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomesHamazaki, JunIemura, SNatsume, TYashiroda, HidekiTanaka, KeijiMurata, ShigeoEMBO J. 25:4524-3624752541Pubmed2014Mechanism of the Rpn13-induced activation of Uch37Jiao, LianyingOuyang, SongyingShaw, NeilSong, GaojieFeng, YingangNiu, FengfengQiu, WeichengZhu, HongtaoHung, Li-WeiZuo, XiaobingEleonora Shtykova, VZhu, PingDong, Yu-HuiXu, RuxiangLiu, Zhi-JieProtein Cell 5:616-309034192Pubmed1997Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasomeLam, Y AXu, WDeMartino, G NCohen, R ENature 385:737-40

UCHL5 binds INO80 complex

The C-terminal extension of UCHL5 (UCH37) binds NFRKB within the INO80 chromatin remodeling complex (Yao et al. 2006, 2008, Conoway & Conoway 2009).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 5689584

nucleoplasmGO0005654

EQUAL

329

EQUAL

Reactome DB_ID: 5689568

INO80 complex [nucleoplasm]

INO80 complex

Reactome DB_ID: 2980912

UniProt:O96019 ACTL6A

ACTL6A

BAF53ACTL6ABAF53AINO80KFUNCTION Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Required for maximal ATPase activity of SMARCA4/BRG1/BAF190A and for association of the SMARCA4/BRG1/BAF190A containing remodeling complex BAF with chromatin/nuclear matrix. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and is required for the proliferation of neural progenitors. During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Putative core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.SUBUNIT Component of numerous complexes with chromatin remodeling and histone acetyltransferase activity. Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 (PubMed:12963728, PubMed:10966108, PubMed:15196461, PubMed:14966270). The NuA4 complex interacts with MYC and the adenovirus E1A protein (PubMed:11509179). Component of a NuA4-related complex which contains EP400, TRRAP/PAF400, SRCAP, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, actin, ACTL6A/BAF53A, VPS72 and YEATS4/GAS41 (PubMed:11509179, PubMed:14966270). Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B) and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific (Probable). Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C (PubMed:9845365, PubMed:18765789). In muscle cells, the BAF complex also contains DPF3. Component of the BAF53 complex, at least composed of ACTL6A/BAF53A, RUVBL1/TIP49, SMARCA2/BRM/BAF190B and TRRAP/PAF400, and which may also include a HAT activity related to, but distinct from, that of KAT5 (PubMed:11839798). Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of SWI/SNF (GBAF) subcomplex, which includes at least BICRA or BICRAL (mutually exclusive), BRD9, SS18, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, SMARCC1/BAF155, and SMARCD1/BAF60A (PubMed:29374058). May be a component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin (PubMed:26601204). Interacts with SMARCA4/BRG1/BAF190A (PubMed:28649782). Interacts with PHF10/BAF45A (By similarity). Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the DBINO domain of INO80 (PubMed:16230350, PubMed:18026119, PubMed:18922472, PubMed:21303910). Interacts with DPF2 (PubMed:28533407).DISEASE ACTL6A mutations have been found in patients with intellectual disability of variable severity, developmental delay, dysmorphic features and digit abnormalities. Additional features may include genitourinary and cardiac defects. The disease phenotype resembles Coffin-Siris syndrome and brachymorphism-onychodysplasia-dysphalangism syndrome.SIMILARITY Belongs to the actin family.

UniProtO96019

EQUAL

429

EQUAL

Reactome DB_ID: 3321849

UniProt:Q96EZ8 MCRS1

MCRS1

MCRS1INO80QMSP58FUNCTION Modulates the transcription repressor activity of DAXX by recruiting it to the nucleolus (PubMed:11948183). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). Putative regulatory component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair. May also be an inhibitor of TERT telomerase activity (PubMed:15044100). Binds to G-quadruplex structures in mRNA (PubMed:16571602). Binds to RNA homopolymer poly(G) and poly(U) (PubMed:16571602).SUBUNIT Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the N-terminus of INO80 (PubMed:16230350, PubMed:18922472, PubMed:21303910). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1 (PubMed:20018852). Interacts with NOP2 (PubMed:9654073). Interacts with PINX1 (PubMed:15044100). Interacts with TERT (PubMed:15044100). Interacts with CCDC85B (PubMed:17014843). Interacts with DAXX (PubMed:11948183). Interacts (via N-terminus) with FMR1 (via phosphorylated form) (PubMed:16571602). Interacts with FXR1 AND FXR2 (PubMed:16571602).SUBUNIT (Microbial infection) Interacts with Herpes simplex virus ICP22.TISSUE SPECIFICITY Detected in testis, and at lower levels in spleen, thymus, prostate, uterus, small intestine, colon and leukocytes.DEVELOPMENTAL STAGE Cell-cycle regulated: levels are highest early in S phase; not detectable in G2.

UniProtQ96EZ8

EQUAL

462

EQUAL

Reactome DB_ID: 3321990

UniProt:P60709 ACTB

ACTB

ACTBFUNCTION Actin is a highly conserved protein that polymerizes to produce filaments that form cross-linked networks in the cytoplasm of cells (PubMed:29581253). Actin exists in both monomeric (G-actin) and polymeric (F-actin) forms, both forms playing key functions, such as cell motility and contraction (PubMed:29581253). In addition to their role in the cytoplasmic cytoskeleton, G- and F-actin also localize in the nucleus, and regulate gene transcription and motility and repair of damaged DNA (PubMed:29925947).SUBUNIT Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix (PubMed:28604741, PubMed:16685646). Each actin can bind to 4 others (PubMed:28604741, PubMed:16685646). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (PubMed:17289661). Component of the BAF complex, which includes at least actin (ACTB), ARID1A, ARID1B/BAF250, SMARCA2, SMARCA4/BRG1, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57 SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more of SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C (PubMed:18765789). In muscle cells, the BAF complex also contains DPF3 (PubMed:18765789). Found in a complex with XPO6, Ran, ACTB and PFN1 (PubMed:14592989). Interacts with XPO6 and EMD (PubMed:15328537). Interacts with ERBB2 (PubMed:21555369). Interacts with GCSAM (PubMed:17823310). Interacts with TBC1D21 (By similarity). Interacts with CPNE1 (via VWFA domain) and CPNE4 (via VWFA domain) (By similarity). Interacts with DHX9 (via C-terminus); this interaction is direct and mediates the attachment to nuclear ribonucleoprotein complexes (PubMed:11687588). Interacts with FAM107A (PubMed:21969592, PubMed:28604741).PTM ISGylated.PTM Oxidation of Met-44 and Met-47 by MICALs (MICAL1, MICAL2 or MICAL3) to form methionine sulfoxide promotes actin filament depolymerization. MICAL1 and MICAL2 produce the (R)-S-oxide form. The (R)-S-oxide form is reverted by MSRB1 and MSRB2, which promote actin repolymerization.PTM Monomethylation at Lys-84 (K84me1) regulates actin-myosin interaction and actomyosin-dependent processes (PubMed:23673617). Demethylation by ALKBH4 is required for maintaining actomyosin dynamics supporting normal cleavage furrow ingression during cytokinesis and cell migration (PubMed:23673617).PTM Methylated at His-73 by SETD3 (PubMed:30526847, PubMed:30626964, PubMed:30785395). Methylation at His-73 is required for smooth muscle contraction of the laboring uterus during delivery (By similarity).PTM (Microbial infection) Monomeric actin is cross-linked by V.cholerae toxins RtxA and VgrG1 in case of infection: bacterial toxins mediate the cross-link between Lys-50 of one monomer and Glu-270 of another actin monomer, resulting in formation of highly toxic actin oligomers that cause cell rounding (PubMed:19015515). The toxin can be highly efficient at very low concentrations by acting on formin homology family proteins: toxic actin oligomers bind with high affinity to formins and adversely affect both nucleation and elongation abilities of formins, causing their potent inhibition in both profilin-dependent and independent manners (PubMed:26228148).MISCELLANEOUS In vertebrates 3 main groups of actin isoforms, alpha, beta and gamma have been identified. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins coexist in most cell types as components of the cytoskeleton and as mediators of internal cell motility.SIMILARITY Belongs to the actin family.CAUTION Was originally thought to be part of the MLL5-L complex, at least composed of KMT2E, STK38, PPP1CA, PPP1CB, PPP1CC, HCFC1, ACTB and OGT (PubMed:19377461). However, the corresponding article has been retracted (PubMed:24336203).

UniProtP60709

EQUAL

375

EQUAL

Reactome DB_ID: 5688910

UniProt:Q9ULG1 INO80

INO80

INOC1KIAA1259INO80INO80AFUNCTION ATPase component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and DNA repair (PubMed:16230350, PubMed:16298340, PubMed:17721549, PubMed:20855601, PubMed:20237820). Binds DNA (PubMed:16298340, PubMed:21303910). As part of the INO80 complex, remodels chromatin by shifting nucleosomes (PubMed:16230350, PubMed:21303910). Regulates transcription upon recruitment by YY1 to YY1-activated genes, where it acts as an essential coactivator (PubMed:17721549). Involved in UV-damage excision DNA repair (PubMed:20855601). The contribution to DNA double-strand break repair appears to be largely indirect through transcriptional regulation (PubMed:20687897). Involved in DNA replication (PubMed:20237820). Required for microtubule assembly during mitosis thereby regulating chromosome segregation cycle (PubMed:20237820).ACTIVITY REGULATION Activated upon binding to double stranded DNA or nucleosomes.SUBUNIT Component of the chromatin remodeling INO80 complex; three different complex modules assemble on different domains of INO80 (PubMed:16230350, PubMed:18026119, PubMed:18922472, PubMed:21303910). Interacts with DDB1 (PubMed:20855601). Interacts with transcriptional repressor protein YY1; the interaction recruits the INO80 complex to YY1 target genes (PubMed:17721549, PubMed:18026119). Interacts with YY1AP1 (PubMed:27939641). Interacts with tubulin alpha (PubMed:20237820).TISSUE SPECIFICITY According to PubMed:10574462, widely expressed. According to PubMed:16298340, specifically expressed in brain, liver and pancreas.DOMAIN The DBINO region is involved in binding to DNA.MISCELLANEOUS Although the ATP-dependent helicase activity displayed by the INO80 complex requires INO80 ATPase activity, it is likely that the helicase function is carried out by the other components of the complex, RUVBL1 and RUVBL2, and not by INO80 itself.SIMILARITY Belongs to the SNF2/RAD54 helicase family.

UniProtQ9ULG1

EQUAL

1556

EQUAL

Reactome DB_ID: 5689559

UniProt:Q53TQ3 INO80D

INO80D

INO80DFUNCTION Putative regulatory component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.SUBUNIT Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the N-terminus of INO80.SIMILARITY Belongs to the INO80D family.

UniProtQ53TQ3

EQUAL

878

EQUAL

Reactome DB_ID: 5689542

UniProt:P0C1Z6 TFPT

TFPT

TFPTINO80FFUNCTION Appears to promote apoptosis in a p53/TP53-independent manner.FUNCTION Putative regulatory component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.SUBUNIT Interacts with NOL3; translocates NOL3 into the nucleus and negatively regulated TFPT-induced cell death (By similarity). Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the N-terminus of INO80.DISEASE A chromosomal aberration involving TFPT is a cause of pre-B-cell acute lymphoblastic leukemia (B-ALL). Inversion inv(19)(p13;q13) with TCF3.

UniProtP0C1Z6

EQUAL

253

EQUAL

Reactome DB_ID: 5689605

UniProt:Q6PI98 INO80C

INO80C

INO80CC18orf37FUNCTION Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.SUBUNIT Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the helicase ATP-binding and the helicase C-terminal domain of INO80. Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10.

UniProtQ6PI98

EQUAL

192

EQUAL

Reactome DB_ID: 4086091

UniProt:P25490 YY1

YY1

YY1INO80SFUNCTION Multifunctional transcription factor that exhibits positive and negative control on a large number of cellular and viral genes by binding to sites overlapping the transcription start site. Binds to the consensus sequence 5'-CCGCCATNTT-3'; some genes have been shown to contain a longer binding motif allowing enhanced binding; the initial CG dinucleotide can be methylated greatly reducing the binding affinity. The effect on transcription regulation is depending upon the context in which it binds and diverse mechanisms of action include direct activation or repression, indirect activation or repression via cofactor recruitment, or activation or repression by disruption of binding sites or conformational DNA changes. Its activity is regulated by transcription factors and cytoplasmic proteins that have been shown to abrogate or completely inhibit YY1-mediated activation or repression. For example, it acts as a repressor in absence of adenovirus E1A protein but as an activator in its presence. Acts synergistically with the SMAD1 and SMAD4 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression (PubMed:15329343). Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions. May play an important role in development and differentiation. Proposed to recruit the PRC2/EED-EZH2 complex to target genes that are transcriptional repressed. Involved in DNA repair. In vitro, binds to DNA recombination intermediate structures (Holliday junctions). Plays a role in regulating enhancer activation (PubMed:28575647).FUNCTION Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair; proposed to target the INO80 complex to YY1-responsive elements.SUBUNIT Interacts with YAF2 through the region encompassing the first and second zinc fingers (PubMed:9016636). Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the DBINO domain of INO80 (PubMed:17721549, PubMed:18026119, PubMed:18922472, PubMed:21303910). Interacts with EED and EZH2; the interactions are indicative for an association with the PRC2/EED-EZH2 complex (PubMed:11158321). Interacts with SFMBT2 (PubMed:23385818). Found in a complex with SMAD1 and SMAD4 (PubMed:15329343). Found in a complex with YY1, SIN3A and HDAC1 (By similarity).PTM Transiently poly-ADP-ribosylated by PARP1 upon DNA damage, with the effect of decreasing affinity of YY1 to its cognate DNA binding sites.PTM Ubiquitinated.SIMILARITY Belongs to the YY transcription factor family.

UniProtP25490

EQUAL

414

EQUAL

Reactome DB_ID: 5689565

UniProt:Q9H981 ACTR8

ACTR8

ARP8ACTR8INO80NFUNCTION Plays an important role in the functional organization of mitotic chromosomes. Exhibits low basal ATPase activity, and unable to polymerize.FUNCTION Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair. Required for the recruitment of INO80 (and probably the INO80 complex) to sites of DNA damage. Strongly prefer nucleosomes and H3-H4 tetramers over H2A-H2B dimers, suggesting it may act as a nucleosome recognition module within the complex.SUBUNIT Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the DBINO domain of INO80. Interacts with ACTR5; the interaction is observed in asynchronous (interphase) cells but not in metaphase-arrested cells indicative for a possible dissociation of the INO80 complex in mitotic cells. Exists as monomers and dimers, but the dimer is most probably the biologically relevant form required for stable interactions with histones that exploits the twofold symmetry of the nucleosome core.SIMILARITY Belongs to the actin family. ARP8 subfamily.

UniProtQ9H981

EQUAL

624

EQUAL

Reactome DB_ID: 5688913

UniProt:Q9H9F9 ACTR5

ACTR5

ACTR5ARP5FUNCTION Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair. Involved in DNA double-strand break repair and UV-damage excision repair.SUBUNIT Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the helicase ATP-binding and the helicase C-terminal domain of INO80. Interacts with DDB1. Interacts with ACTR8; the interaction is observed in asynchronous (interphase) cells but not in metaphase-arrested cells indicative for a possible dissociation of the INO80 complex in mitotic cells.SIMILARITY Belongs to the actin family. ARP5 subfamily.

UniProtQ9H9F9

EQUAL

607

EQUAL

Reactome DB_ID: 5689599

UniProt:Q9C086 INO80B

INO80B

INO80BZNHIT4HMGA1L4PAPA1FUNCTION Induces growth and cell cycle arrests at the G1 phase of the cell cycle.FUNCTION Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.SUBUNIT Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the helicase ATP-binding and the helicase C-terminal domain of INO80. Interacts with RP9.

UniProtQ9C086

EQUAL

356

EQUAL

Reactome DB_ID: 5689578

UniProt:Q6P4R8 NFRKB

NFRKB

INO80GNFRKBFUNCTION Binds to the DNA consensus sequence 5'-GGGGAATCTCC-3'.FUNCTION Putative regulatory component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair. Modulates the deubiquitinase activity of UCHL5 in the INO80 complex.SUBUNIT Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the N-terminus of INO80. Interacts with UCHL5; NFRKB competes with ADRM1 for interaction with UCHL5.TISSUE SPECIFICITY Expressed in thymus, brain, testes, spleen and liver.DOMAIN NFRKB seems to be mostly disordered. The wing-helix like domain doesn't bind DNA.SIMILARITY Belongs to the NFRKB family.

UniProtQ6P4R8

EQUAL

1299

EQUAL

Reactome DB_ID: 5689552

UniProt:Q8NBZ0 INO80E

INO80E

INO80ECCDC95FUNCTION Putative regulatory component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.SUBUNIT Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the N-terminus of INO80.

UniProtQ8NBZ0

EQUAL

244

EQUAL

Reactome DB_ID: 418323

UniProt:Q9Y265 RUVBL1

RUVBL1

TIP49ATIP49RUVBL1INO80HNMP238FUNCTION Possesses single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (3' to 5') activity; hexamerization is thought to be critical for ATP hydrolysis and adjacent subunits in the ring-like structure contribute to the ATPase activity (PubMed:17157868). Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A (PubMed:14966270). This modification may both alter nucleosome-DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription (PubMed:14966270). This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair (PubMed:14966270). The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage (PubMed:14966270). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome (PubMed:24463511). Proposed core component of the chromatin remodeling INO80 complex which exhibits DNA- and nucleosome-activated ATPase activity and catalyzes ATP-dependent nucleosome sliding (PubMed:16230350, PubMed:21303910). Plays an essential role in oncogenic transformation by MYC and also modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex (PubMed:10882073, PubMed:16014379). Essential for cell proliferation (PubMed:14506706). May be able to bind plasminogen at cell surface and enhance plasminogen activation (PubMed:11027681).SUBUNIT Forms homohexameric rings. Can form a dodecamer with RUVBL2 made of two stacked hexameric rings; however, even though RUVBL1 and RUVBL2 are present in equimolar ratio, the oligomeric status of each hexamer is not known. Oligomerization may regulate binding to nucleic acids and conversely, binding to nucleic acids may affect the dodecameric assembly. Interacts with the transcriptional activation domain of MYC. Component of the RNA polymerase II holoenzyme complex. May also act to bridge the LEF1/TCF1-CTNNB1 complex and TBP. Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6. The NuA4 complex interacts with MYC and the adenovirus E1A protein. RUVBL1 interacts with EP400. Component of a NuA4-related complex which contains EP400, TRRAP/PAF400, SRCAP, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, actin, ACTL6A/BAF53A, VPS72 and YEATS4/GAS41. Component of the BAF53 complex, at least composed of ACTL6A/BAF53A, RUVBL1/TIP49, SMARCA2/BRM, and TRRAP/PAF400. Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Associates with alpha and gamma tubulins, particularly during metaphase and early anaphase. Interacts with NPAT. Component of the chromatin-remodeling INO80 complex; specifically part of a complex module associated with the helicase ATP-binding and the helicase C-terminal domain of INO80. Interacts with IGHMBP2. Interacts with OFD1. Interacts with HINT1. Component of a complex with USP49 and PSMC5. Component of a SWR1-like complex. Component of the R2TP complex composed at least of PIHD1, RUVBL1, RUVBL2 and RPAP3 (PubMed:20864032). Interacts with PIH1D1 (PubMed:17636026). Interacts with ITFG1 (PubMed:25437307). Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). The RUVBL1/RUVBL2 complex interacts with ZNHIT1 (via HIT-type zinc finger), ZNHIT3 (via HIT-type zinc finger), ZNHIT6 (via HIT-type zinc finger) and DDX59/ZNHIT5 (via HIT-type zinc finger) in the presence of ADP (PubMed:28561026).TISSUE SPECIFICITY Ubiquitously expressed with high expression in heart, skeletal muscle and testis.DOMAIN Binding to MYC is dependent on a Myc domain essential for oncogenic activity.MISCELLANEOUS High level of autoantibodies against RUVBL1 are detected in sera of patients with autoimmune diseases such as polymyositis/dermatomyosistis and autoimmune hepatitis.SIMILARITY Belongs to the RuvB family.

UniProtQ9Y265

EQUAL

456

EQUAL

Reactome Database ID Release 755689568Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689568ReactomeR-HSA-5689568

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689568.1

Reactome DB_ID: 5689602

UCHL5:INO80 complex [nucleoplasm]

UCHL5:INO80 complex

Reactome DB_ID: 5689584

EQUAL

329

EQUAL

Reactome DB_ID: 5689568

Reactome Database ID Release 755689602Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689602ReactomeR-HSA-5689602

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689602.2Reactome Database ID Release 755689544Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689544ReactomeR-HSA-5689544

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689544.219062292Pubmed2009The INO80 chromatin remodeling complex in transcription, replication and repairConaway, Ronald CConaway, Joan WelikyTrends Biochem. Sci. 34:71-718922472Pubmed2008Distinct modes of regulation of the Uch37 deubiquitinating enzyme in the proteasome and in the Ino80 chromatin-remodeling complexYao, TingtingSong, LJin, JingjiCai, YongTakahashi, HidehisaSwanson, Selene KWashburn, Michael PFlorens, Laurence AConaway, Ronald CCohen, Robert EConaway, Joan WMol. Cell 31:909-1716906146Pubmed2006Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrm1Yao, TingtingSong, LXu, WeiDeMartino, George NFlorens, Laurence ASwanson, Selene KWashburn, Michael PConaway, Ronald CConaway, Joan WelikyCohen, Robert ENat. Cell Biol. 8:994-1002

BAP1 binds BAP1-interacting complex

BRCA1-associated protein 1 (BAP1) is a ubiquitin COOH-terminal hydrolase that was initially identified as a protein that binds the RING finger domain of the breast and ovarian tumor suppressor BRCA1. BAP1 is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway (Murali et al. 2013). The C-terminal coiled coil motif of BAP1 directly interacts with the zinc fingers of the transcription factor Yin Yang 1 (YY1) (Yu et al. 2010), part of a multiprotein complex containing numerous transcription factors and cofactors including the transcriptional regulator Host cell factor 1 (HCFC1), which binds the N-terminal portion of BAP1 (Misaghi et al. 2009, Machida et al. 2009). HCFC1 is a chromatin-associated protein initially identified as part of a multiprotein complex comprising the viral coactivator VP16 and the POU domain transcription factor POU2F1. During herpes simplex virus infection, this complex is recruited to the enhancer/promoter of the immediate-early gene to activate viral gene expression (Kristie et al. 2010). The C-terminal extension of UCHL5 mediates association with Adrm1/Rpn13 of the proteasomal 19S regulatory subunit and with NFRKB of the INO80 chromatin remodeling complex. The extreme C-terminal segment of BAP1 is 38% identical to the C-terminus of UCHL5 (UCH37) and is necessary for binding to YY1 (Yu et al. 2010).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 5689665

UniProt:Q92560 BAP1

BAP1

hucep-6BAP1KIAA0272FUNCTION Deubiquitinating enzyme that plays a key role in chromatin by mediating deubiquitination of histone H2A and HCFC1 (PubMed:12485996, PubMed:18757409, PubMed:20436459, PubMed:25451922). Catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1) (PubMed:20436459, PubMed:25451922). Does not deubiquitinate monoubiquitinated histone H2B (PubMed:20436459). Acts as a regulator of cell growth by mediating deubiquitination of HCFC1 N-terminal and C-terminal chains, with some specificity toward 'Lys-48'-linked polyubiquitin chains compared to 'Lys-63'-linked polyubiquitin chains (PubMed:19188440, PubMed:19815555). Deubiquitination of HCFC1 does not lead to increase stability of HCFC1 (PubMed:19188440, PubMed:19815555). Interferes with the BRCA1 and BARD1 heterodimer activity by inhibiting their ability to mediate ubiquitination and autoubiquitination (PubMed:19117993). It however does not mediate deubiquitination of BRCA1 and BARD1 (PubMed:19117993). Able to mediate autodeubiquitination via intramolecular interactions to couteract monoubiquitination at the nuclear localization signal (NLS), thereby protecting it from cytoplasmic sequestration (PubMed:24703950). Acts as a tumor suppressor (PubMed:9528852).SUBUNIT Component of the PR-DUB complex, at least composed of BAP1 and ASXL1 (PubMed:20436459). Interacts with BRCA1 (via the RING finger) (PubMed:19117993, PubMed:9528852). Interacts (via HBM-like motif) with HCFC1 (PubMed:19188440, PubMed:19815555). Interacts (when phosphorylated at Thr-493) with FOXK1 (PubMed:25451922). Interacts (when phosphorylated at Thr-493) with FOXK2; leading to recruit the PR-DUB complex and repress FOXK2 target genes (PubMed:24748658, PubMed:25451922).TISSUE SPECIFICITY Highly expressed in testis, placenta and ovary. Expressed in breast.PTM Ubiquitinated: monoubiquitinated at multiple site of its nuclear localization signal (NLS) BY UBE2O, leading to cytoplasmic retention. Able to mediate autodeubiquitination via intramolecular interactions to couteract cytoplasmic retention.SIMILARITY Belongs to the peptidase C12 family. BAP1 subfamily.CAUTION According to a report, interaction with FOXK2 is not dependent on phosphorylation of BAP1 (PubMed:24748658). However, it was later shown that phosphorylation at Thr-493 promotes interaction with FOXK2 (PubMed:25451922).

UniProtQ92560

EQUAL

729

EQUAL

Reactome DB_ID: 5689653

BAP1-interacting complex [nucleoplasm]

BAP1-interacting complex

Reactome DB_ID: 5689678

BAP1-interacting core complex [nucleoplasm]

BAP1-interacting core complex

Converted from EntitySet in Reactome

Reactome DB_ID: 5689657

FOXK1,FOXK2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityFOXK1 [nucleoplasm]FOXK2 [nucleoplasm]

UniProtP85037UniProtQ01167Converted from EntitySet in Reactome

Reactome DB_ID: 5689640

ASXL1,ASXL2 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityASXL1 [nucleoplasm]ASXL2 [nucleoplasm]

UniProtQ8IXJ9UniProtQ76L83

Reactome DB_ID: 3321845

UniProt:O15294 OGT

OGT

OGTFUNCTION Catalyzes the transfer of a single N-acetylglucosamine from UDP-GlcNAc to a serine or threonine residue in cytoplasmic and nuclear proteins resulting in their modification with a beta-linked N-acetylglucosamine (O-GlcNAc) (PubMed:26678539, PubMed:23103939, PubMed:21240259, PubMed:21285374, PubMed:15361863). Glycosylates a large and diverse number of proteins including histone H2B, AKT1, EZH2, PFKL, KMT2E/MLL5, MAPT/TAU and HCFC1. Can regulate their cellular processes via cross-talk between glycosylation and phosphorylation or by affecting proteolytic processing (PubMed:21285374). Probably by glycosylating KMT2E/MLL5, stabilizes KMT2E/MLL5 by preventing its ubiquitination (PubMed:26678539). Involved in insulin resistance in muscle and adipocyte cells via glycosylating insulin signaling components and inhibiting the 'Thr-308' phosphorylation of AKT1, enhancing IRS1 phosphorylation and attenuating insulin signaling (By similarity). Involved in glycolysis regulation by mediating glycosylation of 6-phosphofructokinase PFKL, inhibiting its activity (PubMed:22923583). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. Plays a key role in chromatin structure by mediating O-GlcNAcylation of 'Ser-112' of histone H2B: recruited to CpG-rich transcription start sites of active genes via its interaction with TET proteins (TET1, TET2 or TET3) (PubMed:22121020, PubMed:23353889). As part of the NSL complex indirectly involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). O-GlcNAcylation of 'Ser-75' of EZH2 increases its stability, and facilitating the formation of H3K27me3 by the PRC2/EED-EZH2 complex (PubMed:24474760). Regulates circadian oscillation of the clock genes and glucose homeostasis in the liver. Stabilizes clock proteins ARNTL/BMAL1 and CLOCK through O-glycosylation, which prevents their ubiquitination and subsequent degradation. Promotes the CLOCK-ARNTL/BMAL1-mediated transcription of genes in the negative loop of the circadian clock such as PER1/2 and CRY1/2 (PubMed:12150998, PubMed:19451179, PubMed:20018868, PubMed:20200153, PubMed:21285374, PubMed:15361863). O-glycosylates HCFC1 and regulates its proteolytic processing and transcriptional activity (PubMed:21285374, PubMed:28584052, PubMed:28302723). Regulates mitochondrial motility in neurons by mediating glycosylation of TRAK1 (By similarity). Glycosylates HOXA1 (By similarity). O-glycosylates FNIP1 (PubMed:30699359).ACTIVITY REGULATION Subject to product inhibition by UDP.PATHWAY Protein modification; protein glycosylation.SUBUNIT Monomer; may exist in different oligomerization states in cells (PubMed:21240259). Homotrimer, oligomerizes via TPR repeats 6 and 7. Trimerization is not necessary for activity in vitro, however it increases affinity for UDP-GlcNAc (By similarity). Component of a THAP1/THAP3-HCFC1-OGT complex (PubMed:20200153). Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1 (PubMed:20018852). Interacts directly with HCFC1; the interaction O-glycosylates HCFC1, regulates its proteolytic processing and transcriptional activity and, in turn, stabilizes OGT in the nucleus (PubMed:12670868, PubMed:20200153, PubMed:21285374, PubMed:23353889). Interacts (via TPRs 1-6) with SIN3A; the interaction mediates transcriptional repression in parallel with histone deacetylase (PubMed:12150998). Interacts (via TPR 5-6) with TET1, TET2 and TET3 (PubMed:23353889, PubMed:23222540). Interacts (via TPR repeats 6 and 7) with ATXN10 (By similarity). Interacts with histone H2B (PubMed:22121020). Interacts with ARNTL/BMAL1. Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1. Interacts with SINHCAF (By similarity). Component of a complex composed of KMT2E/MLL5 (isoform 3), OGT (isoform 1) and USP7; the complex stabilizes KMT2E/MLL5, preventing KMT2E/MLL5 ubiquitination and proteosomal-mediated degradation (PubMed:26678539). Isoform 1 interacts (via TRP repeats) with isoform 3 KMT2E/MLL5 (via N-terminus) (PubMed:26678539, PubMed:23629655). Isoform 1 interacts with USP7 (PubMed:26678539). Interacts with TRAK1; this interaction is not required for glycosylation of TRAK1 by this protein. Found in a complex with KIF5B, RHOT1, RHOT2 and TRAK1 (PubMed:24995978). Interacts (via TPR repeats domain) with HOXA1; the interaction takes place mainly in the nucleus (By similarity).SUBUNIT (Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein Tax; this interaction increases Tax interacting partner CREB1 O-GlcNAcylation.TISSUE SPECIFICITY Highly expressed in pancreas and to a lesser extent in skeletal muscle, heart, brain and placenta. Present in trace amounts in lung and liver.INDUCTION Induction of the nucleocytoplasmic OGT (ncOGT) isoform in the liver on glucose deprivation is mediated by the decreased hexosamine biosynthesis pathway (HBP) flux.DOMAIN The TPR repeat domain is required for substrate binding and oligomerization.PTM Ubiquitinated, leading to its proteasomal degradation.PTM Phosphorylation on Ser-3 or Ser-4 by GSK3-beta positively regulates its activity.DISEASE Regulation of OGT activity and altered O-GlcNAcylations are implicated in diabetes and Alzheimer disease. O-GlcNAcylation of AKT1 affects insulin signaling and, possibly diabetes. Reduced O-GlcNAcylations and resulting increased phosphorylations of MAPT/TAU are observed in Alzheimer disease (AD) brain cerebrum.SIMILARITY Belongs to the glycosyltransferase 41 family. O-GlcNAc transferase subfamily.CAUTION Was originally thought to be part of the MLL5-L complex, at least composed of KMT2E, STK38, PPP1CA, PPP1CB, PPP1CC, HCFC1, ACTB and OGT (PubMed:19377461). However, the corresponding article has been retracted (PubMed:24336203).

UniProtO15294

EQUAL

1046

EQUAL

Reactome DB_ID: 1592209

UniProt:P51610 HCFC1

HCFC1

HCF1HFC1HCFC1FUNCTION Involved in control of the cell cycle (PubMed:10629049, PubMed:10779346, PubMed:15190068, PubMed:16624878, PubMed:23629655). Also antagonizes transactivation by ZBTB17 and GABP2; represses ZBTB17 activation of the p15(INK4b) promoter and inhibits its ability to recruit p300 (PubMed:10675337, PubMed:12244100). Coactivator for EGR2 and GABP2 (PubMed:12244100, PubMed:14532282). Tethers the chromatin modifying Set1/Ash2 histone H3 'Lys-4' methyltransferase (H3K4me) and Sin3 histone deacetylase (HDAC) complexes (involved in the activation and repression of transcription, respectively) together (PubMed:12670868). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1 (PubMed:20200153). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). Recruits KMT2E/MLL5 to E2F1 responsive promoters promoting transcriptional activation and thereby facilitates G1 to S phase transition (PubMed:23629655).FUNCTION (Microbial infection) In case of human herpes simplex virus (HSV) infection, HCFC1 forms a multiprotein-DNA complex with the viral transactivator protein VP16 and POU2F1 thereby enabling the transcription of the viral immediate early genes.SUBUNIT Composed predominantly of six polypeptides ranging from 110 to 150 kDa and a minor 300 kDa polypeptide (PubMed:10920196). The majority of N- and C-terminal cleavage products remain tightly, albeit non-covalently, associated (PubMed:10920196). Interacts with POU2F1, CREB3, ZBTB17, EGR2, E2F4, CREBZF, SP1, GABP2, Sin3 HDAC complex (SIN3A, HDAC1, HDAC2, SUDS3), SAP30, SIN3B and FHL2 (PubMed:9271389, PubMed:9389645, PubMed:10675337, PubMed:10976766, PubMed:10629049, PubMed:10871379, PubMed:10984507, PubMed:12244100, PubMed:14532282, PubMed:12670868, PubMed:15705566, PubMed:16624878). Component of a MLL1 complex, composed of at least the core components KMT2A/MLL1, ASH2L, HCFC1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, DPY30, E2F6, HCFC2, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MEN1, MGA, KAT8, PELP1, PHF20, PRP31, RING2, RUVBL1, RUVBL2, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15199122, PubMed:15960975). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1 (PubMed:20200153). Interacts directly with THAP3 (via its HBM) (PubMed:20200153). Interacts (via the Kelch-repeat domain) with THAP1 (via the HBM); the interaction recruits HCHC1 to the RRM1 (PubMed:20200153). Interacts directly with OGT; the interaction, which requires the HCFC1 cleavage site domain, glycosylates and promotes the proteolytic processing of HCFC1, retains OGT in the nucleus and impacts the expression of herpes simplex virus immediate early viral genes (PubMed:12670868, PubMed:21285374, PubMed:23353889). Component of the SET1 complex, at least composed of the catalytic subunit (SETD1A or SETD1B), WDR5, WDR82, RBBP5, ASH2L, CXXC1, HCFC1 and DPY30 (PubMed:17998332, PubMed:18838538). Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1 (PubMed:20018852). Component of a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5; the complex is formed as a result of interactions between components of a nuclear receptor-mediated transcription complex and a histone methylation complex (PubMed:19131338). Within the complex interacts with ZNF335 (PubMed:19131338). Interacts with TET2 and TET3 (PubMed:23353889). Interacts with HCFC1R1 (PubMed:12235138). Interacts with THAP11 (By similarity). Interacts (via Kelch domain) with KMT2E/MLL5 isoform 3 (via HBM motif) (PubMed:23629655). Interacts with E2F1 (PubMed:23629655).SUBUNIT (Microbial infection) Associates with the VP16-induced complex; binding to HCFC1 activates the viral transcriptional activator VP16 for association with POU2F1, to form a multiprotein-DNA complex responsible for activating transcription of the viral immediate early genes (PubMed:10629049). Interacts with the viral transactivator protein VP16 (PubMed:9271389, PubMed:9389645, PubMed:10629049).TISSUE SPECIFICITY Highly expressed in fetal tissues and the adult kidney. Present in all tissues tested.DOMAIN The HCF repeat is a highly specific proteolytic cleavage signal.DOMAIN The kelch repeats fold into a 6-bladed kelch beta-propeller called the beta-propeller domain which mediates interaction with HCFC1R1.PTM Proteolytically cleaved at one or several PPCE--THET sites within the HCF repeats. Further cleavage of the primary N- and C-terminal chains results in a 'trimming' and accumulation of the smaller chains. Cleavage is promoted by O-glycosylation.PTM O-glycosylated. GlcNAcylation by OGT promotes proteolytic processing.PTM Ubiquitinated. Lys-1807 and Lys-1808 are ubiquitinated both via 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. BAP1 mediated deubiquitination of 'Lys-48'-linked polyubiquitin chains; deubiquitination by BAP1 does not seem to stabilize the protein.CAUTION Was originally thought to be part of the MLL5-L complex, at least composed of KMT2E, STK38, PPP1CA, PPP1CB, PPP1CC, HCFC1, ACTB and OGT (PubMed:19377461). However, the corresponding article has been retracted (PubMed:24336203).

UniProtP51610

EQUAL

2035

EQUAL

Reactome Database ID Release 755689678Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689678ReactomeR-HSA-5689678

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689678.2

Reactome DB_ID: 4086091

EQUAL

414

EQUAL

Reactome Database ID Release 755689653Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689653ReactomeR-HSA-5689653

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689653.2

Reactome DB_ID: 5689682

BAP1:BAP1-interacting complex [nucleoplasm]

BAP1:BAP1-interacting complex

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome DB_ID: 5689653

Reactome Database ID Release 755689682Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689682ReactomeR-HSA-5689682

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689682.2Reactome Database ID Release 755689630Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689630ReactomeR-HSA-5689630

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689630.219188440Pubmed2009Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1Misaghi, ShahramOttosen, SørenIzrael-Tomasevic, AnitaArnott, DavidLamkanfi, MohamedLee, JamesLiu, JinfengO'Rourke, KarenDixit, Vishva MWilson, Angus CMol. Cell. Biol. 29:2181-9219815555Pubmed2009The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1Machida, Yuichi JMachida, YukaVashisht, Ajay AWohlschlegel, James ADutta, AnindyaJ. Biol. Chem. 284:34179-8819117993Pubmed2009BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activityNishikawa, HiroyukiWu, WenwenKoike, AyakaKojima, RyokoGomi, HiromichiFukuda, MamoruOhta, TomohikoCancer Res. 69:111-920805357Pubmed2010The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expressionYu, HelenMashtalir, NazarDaou, SalimaHammond-Martel, IanRoss, JulieSui, GuangchaoHart, Gerald WRauscher, Frank JDrobetsky, ElliotMilot, EricShi, YangAffar, El BachirMol. Cell. Biol. 30:5071-8523277170Pubmed2013Tumours associated with BAP1 mutationsMurali, RajmohanWiesner, ThomasScolyer, Richard APathology 45:116-269528852Pubmed1998BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppressionJensen, D EProctor, MMarquis, S TGardner, H PHa, S IChodosh, L AIshov, A MTommerup, NVissing, HSekido, YMinna, JBorodovsky, ASchultz, D CWilkinson, K DMaul, G GBarlev, NBerger, S LPrendergast, G CRauscher, F JOncogene 16:1097-11219682612Pubmed2010Control of alpha-herpesvirus IE gene expression by HCF-1 coupled chromatin modification activitiesKristie, Thomas MLiang, YVogel, Jodi LBiochim. Biophys. Acta 1799:257-65

BAP1 binds BRCA1:BARD1

BRCA1-associated protein 1 (BAP1) is a ubiquitin COOH-terminal hydrolase that was initially identified as a protein that binds the RING finger domain of the breast and ovarian tumor suppressor BRCA1. The extreme C-terminal segment of BAP1, which is 38% identical to the C-terminus of UCHL5 (UCH37), is necessary for binding to BRCA1 (Jensen et al. 1998). The N-terminal portion of BAP1 binds BARD1 (Nishikawa et al. 2009). BARD1:BRCA1 constitutes a RING heterodimer E3 ligase. BAP1 binding with BARD1 interferes with BARD1-BRCA association. BAP1 can also deubiquitinate the polyubiquitin chains mediated by BRCA1:BARD1 (Nishikawa et al. 2009). BAP1 is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway (Murali et al. 2013).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome DB_ID: 5659775

UniProt:Q99728 BARD1

BARD1

BARD1FUNCTION E3 ubiquitin-protein ligase. The BRCA1-BARD1 heterodimer specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Plays a central role in the control of the cell cycle in response to DNA damage. Acts by mediating ubiquitin E3 ligase activity that is required for its tumor suppressor function. Also forms a heterodimer with CSTF1/CSTF-50 to modulate mRNA processing and RNAP II stability by inhibiting pre-mRNA 3' cleavage.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homo- and heterodimer. Heterodimer (RING-type zinc finger) with BRCA1. Heterodimer (via ANK repeats and BRCT domains) with CSTF1/CSTF-50. Component of the BRCA1-A complex, at least composed of the BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Interacts with UBXN1.PTM Processed during apoptosis. The homodimer is more susceptible to proteolytic cleavage than the BARD1/BRCA1 heterodimer.CAUTION It is uncertain whether Met-1 or Met-26 is the initiator.

UniProtQ99728

EQUAL

777

EQUAL

Reactome DB_ID: 5690771

BAP1:BARD1 [nucleoplasm]

BAP1:BARD1

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome DB_ID: 5659775

EQUAL

777

EQUAL

Reactome Database ID Release 755690771Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690771ReactomeR-HSA-5690771

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690771.2Reactome Database ID Release 755689649Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689649ReactomeR-HSA-5689649

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689649.2

BAP1 binds Ub-HCFC1

BRCA1 associated protein 1 (BAP1) is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway (Eletr & Wilkinson 2011, Murali et al. 2013). BAP1 mediates the deubiquitination of Host cell factor 1 (HCFC1) thereby regulating cell growth, though deubiquitination of HCFC1 does not lead to increased HCFC1 stability. HCFC1 is K48 and K63 ubiquitinated. The major site of linkage are lysines 1807 and 1808 (Machida et al. 2009).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome DB_ID: 5690821

ubiquitinylated lysine (K48-polyUb, K63-polyUb [nucleoplasm]) at 1807

1807

EQUAL

ubiquitinylated lysine [MOD:01148]

EQUAL

2035

EQUAL

Reactome DB_ID: 5690760

BAP1:K48polyUb,K63polyUb-HCFC1 [nucleoplasm]

BAP1:K48polyUb,K63polyUb-HCFC1

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome DB_ID: 5690821

ubiquitinylated lysine (K48-polyUb, K63-polyUb [nucleoplasm]) at 1807

1807

EQUAL

2035

EQUAL

Reactome Database ID Release 755690760Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690760ReactomeR-HSA-5690760

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690760.2Reactome Database ID Release 755690785Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690785ReactomeR-HSA-5690785

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690785.221484256Pubmed2011An emerging model for BAP1's role in regulating cell cycle progressionEletr, Ziad MWilkinson, Keith DCell Biochem. Biophys. 60:3-11

BAP1:Ub-HCFC1 deubiquitinates BAP1:Ub-HCFC1

BRCA1 associated protein 1 (BAP1) is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway (Murali et al. 2013). BAP1 mediates the deubiquitination of Host cell factor 1 (HCFC1) thereby regulating cell growth (Eletr & Wilinson 2011), though deubiquitination of HCFC1 does not lead to increased HCFC1 stability. HCFC1 is K48 and K63 ubiquitinated; the major site of linkage are lysines 1807 and 1808 (Machida et al. 2009).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 113518

water [ChEBI:15377]

water

ChEBI15377

Reactome DB_ID: 5690760

Reactome DB_ID: 5690817

BAP1:HCFC1 [nucleoplasm]

BAP1:HCFC1

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome DB_ID: 1592209

EQUAL

2035

EQUAL

Reactome Database ID Release 755690817Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690817ReactomeR-HSA-5690817

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690817.2Converted from EntitySet in Reactome

Reactome DB_ID: 6782528

K48-polyUb, K63-polyUb [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 5690760

GO0004843

GO molecular function

Reactome Database ID Release 755690780Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690780Reactome Database ID Release 755690759Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690759ReactomeR-HSA-5690759

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690759.2

Histone H2A is dubiquitinated by the PR-DUB complex

BAP1 is the catalytic component of the PR-DUB complex, which deubiquitinates Lysine-120 monoubiquitinated Histone H2A (H2AK119ub1) (Scheuermann et al. 2010). The PR-DUB complex consists of BAP1, ASXL1/2, KDM1B, FOXK1/2, HCFC1 and MBD5/6 (Yu et al. 2010, Dey et al. 2012, Baymaz et al. 2014).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 113518

Converted from EntitySet in Reactome

Reactome DB_ID: 6782529

Ub-histone H2A [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Converted from EntitySet in Reactome

Reactome DB_ID: 4657028

Histone H2A [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Ub [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRPS27A(1-76) [nucleoplasm]UBB(77-152) [nucleoplasm]UBC(229-304) [nucleoplasm]UBC(457-532) [nucleoplasm]UBC(533-608) [nucleoplasm]UBB(1-76) [nucleoplasm]UBC(305-380) [nucleoplasm]UBC(1-76) [nucleoplasm]UBB(153-228) [nucleoplasm]UBC(609-684) [nucleoplasm]UBA52(1-76) [nucleoplasm]UBC(153-228) [nucleoplasm]UBC(77-152) [nucleoplasm]UBC(381-456) [nucleoplasm]

UniProtP62979UniProtP0CG47UniProtP0CG48UniProtP62987PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 5690807

PR-DUB complex [nucleoplasm]

PR-DUB complex

Converted from EntitySet in Reactome

Reactome DB_ID: 5689657

Reactome DB_ID: 5423072

UniProt:Q8NB78 KDM1B

KDM1B

KDM1BC6orf193LSD2AOF1FUNCTION Histone demethylase that demethylates 'Lys-4' of histone H3, a specific tag for epigenetic transcriptional activation, thereby acting as a corepressor. Required for de novo DNA methylation of a subset of imprinted genes during oogenesis. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Demethylates both mono- and di-methylated 'Lys-4' of histone H3. Has no effect on tri-methylated 'Lys-4', mono-, di- or tri-methylated 'Lys-9', mono-, di- or tri-methylated 'Lys-27', mono-, di- or tri-methylated 'Lys-36' of histone H3, or on mono-, di- or tri-methylated 'Lys-20' of histone H4.ACTIVITY REGULATION Histone H3K4me1 and H3K4me2 demethylase activity is enhanced by GLYR1.SUBUNIT Does not form a complex with RCOR1/CoREST (By similarity). Interacts with its cofactor GLYR1 at nucleosomes; this interaction stimulates H3K4me1 and H3K4me2 demethylation (PubMed:23260659).DOMAIN The SWIRM domain may act as an anchor site for a histone tail.SIMILARITY Belongs to the flavin monoamine oxidase family.

UniProtQ8NB78

EQUAL

822

EQUAL

Reactome DB_ID: 5690793

PR-DUB core complex [nucleoplasm]

PR-DUB core complex

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 5689640

Reactome Database ID Release 755690793Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690793ReactomeR-HSA-5690793

Reactome DB_ID: 5690767

MBD5,MBD6 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMBD5 [nucleoplasm]MBD6 [nucleoplasm]

UniProtQ9P267UniProtQ96DN6

Reactome DB_ID: 1592209

EQUAL

2035

EQUAL

Reactome Database ID Release 755690807Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690807ReactomeR-HSA-5690807

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690807.2Reactome Database ID Release 755690792Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690792Reactome Database ID Release 755690790Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690790ReactomeR-HSA-5690790

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690790.320436459Pubmed2010Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUBScheuermann, Johanna Cde Ayala Alonso, Andrés GaytánOktaba, KatarzynaLy-Hartig, NgaMcGinty, Robert KFraterman, SvenWilm, MatthiasMuir, Tom WMüller, JürgNature 465:243-722878500Pubmed2012Loss of the tumor suppressor BAP1 causes myeloid transformationDey, AnweshaSeshasayee, DhayaNoubade, RajkumarFrench, Dorothy MLiu, JinfengChaurushiya, Mira SKirkpatrick, Donald SPham, Victoria CLill, Jennie RBakalarski, Corey EWu, JianshengPhu, LilianKatavolos, PaulaLaFave, Lindsay MAbdel-Wahab, OmarModrusan, ZoraSeshagiri, SomasekarDong, KenLin, ZhonghuaBalazs, MercedeszSuriben, RowenaNewton, KimHymowitz, SarahGarcia-Manero, GuillermoMartin, FlaviusLevine, Ross LDixit, Vishva MScience 337:1541-624634419Pubmed2014MBD5 and MBD6 interact with the human PR-DUB complex through their methyl-CpG-binding domainBaymaz, H IremFournier, AlexandraLaget, SophieJi, ZonglingJansen, Pascal W T CSmits, Arne HFerry, LaureMensinga, AnneloesPoser, InaSharrocks, AndrewDefossez, Pierre-AntoineVermeulen, MichielProteomics 14:2179-89

UCHL1, UCHL3 cleave ubiquitin adducts

UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers (Wilkinson et al. 1989, Wada et al. 1998, Larsen et al. 1998). This liberates small molecule nucleophiles that may have inadvertently reacted with Ub C-terminal thiolesters. Because these enzymes can cleave small peptides from the C-terminus of Ub, they could also function in recycling Ub from incomplete proteasomal or lysosomal protein degradation. UCHL3, but not UCHL1, is able to cleave the C-terminus of Neural precursor cell expressed developmentally downregulated protein 8 (NEDD8), a ubiquitin-like protein that activates the largest ubiquitin E3 ligase family, the cullin-RING ligases (Wada et al. 1998, Enchev et al. 2015). UCHL1 and 3 are specifically expressed in neurons, cells of the diffuse neuroendocrine system and their tumors. A polymorphism (S18Y) in UCHL1 is associated with a reduced risk for Parkinson's disease (Wang et al. 2002) and its overexpression is protective in models of Alzheimer's disease (Gong et al. 2006). UCHL1 has been shown to interact with alpha-synuclein, but as a ubiquitin ligase rather than as a ubiquitin hydrolase (Liu et al. 2002). It is K63-polyubiquitinated by Parkin in cooperation with the Ubc13/Uev1a E2 ubiquitin-conjugating enzyme complex, promoting UCH-L1 degradation by the autophagy-lysosome pathway (McKeon et al. 2015).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 29356

Reactome DB_ID: 6782633

UCHL1,UCHL3:Ub-Lys [cytosol]

UCHL1,UCHL3:Ub-Lys

Converted from EntitySet in Reactome

Reactome DB_ID: 8869028

Ub-Lys [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityN6-glycyl-L-lysine-RPS27A(1-76) [cytosol]N6-glycyl-L-lysine-UBC(381-456) [cytosol]N6-glycyl-L-lysine-UBC(457-532) [cytosol]N6-glycyl-L-lysine-UBC(533-608) [cytosol]N6-glycyl-L-lysine-UBA52(1-76) [cytosol]N6-glycyl-L-lysine-UBC(77-152) [cytosol]N6-glycyl-L-lysine-UBC(305-380) [cytosol]N6-glycyl-L-lysine-UBB(77-152) [cytosol]N6-glycyl-L-lysine-UBC(153-228) [cytosol]N6-glycyl-L-lysine-UBC(1-76) [cytosol]N6-glycyl-L-lysine-UBB(1-76) [cytosol]N6-glycyl-L-lysine-UBB(153-228) [cytosol]N6-glycyl-L-lysine-UBC(229-304) [cytosol]N6-glycyl-L-lysine-UBC(609-684) [cytosol]

Converted from EntitySet in Reactome

Reactome DB_ID: 5690768

UCHL1,UCHL3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUCHL1 [cytosol]UCHL3 [cytosol]

UniProtP09936UniProtP15374Reactome Database ID Release 756782633Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782633ReactomeR-HSA-6782633

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782633.2

Reactome DB_ID: 1131871

cytoplasmGO0005737

L-lysinium(1+) [ChEBI:32551]

L-lysinium(1+)

L-lysine monocationInChI=1S/C6H14N2O2/c7-4-2-1-3-5(8)6(9)10/h5H,1-4,7-8H2,(H,9,10)/p+1/t5-/m0/s1C6H15N2O2L-lysine[NH3+]CCCC[C@H]([NH3+])C([O-])=OL-lysiniumKDXKERNSBIXSRK-YFKPBYRVSA-O147.19558(2S)-2,6-diammoniohexanoate

ChEBI32551

Reactome DB_ID: 6782592

UCHL1,UCHL3:Ub [cytosol]

UCHL1,UCHL3:Ub

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Ub [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBC(229-304) [cytosol]UBC(153-228) [cytosol]UBC(609-684) [cytosol]UBB(77-152) [cytosol]UBC(1-76) [cytosol]UBC(457-532) [cytosol]UBC(77-152) [cytosol]UBC(305-380) [cytosol]UBA52(1-76) [cytosol]RPS27A(1-76) [cytosol]UBB(153-228) [cytosol]UBC(533-608) [cytosol]UBC(381-456) [cytosol]UBB(1-76) [cytosol]

Converted from EntitySet in Reactome

Reactome DB_ID: 5690768

Reactome Database ID Release 756782592Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782592ReactomeR-HSA-6782592

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782592.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782633

Reactome Database ID Release 755690781Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690781Reactome Database ID Release 755690319Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690319ReactomeR-HSA-5690319

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690319.29521656Pubmed1998Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolasesLarsen, C NKrantz, B AWilkinson, K DBiochemistry 37:3358-6812408865Pubmed2002The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibilityLiu, YichinFallon, LaraLashuel, Hilal ALiu, ZhihuaLansbury, Peter TCell 111:209-1825403879Pubmed2015Parkin-mediated K63-polyubiquitination targets ubiquitin C-terminal hydrolase L1 for degradation by the autophagy-lysosome systemMcKeon, Jeanne ESha, DiLi, LianChin, Lih-ShenCell. Mol. Life Sci. 72:1811-2425531226Pubmed2015Protein neddylation: beyond cullin-RING ligasesEnchev, Radoslav ISchulman, Brenda APeter, MatthiasNat. Rev. Mol. Cell Biol. 16:30-449790970Pubmed1998Cleavage of the C-terminus of NEDD8 by UCH-L3Wada, HKito, KCaskey, L SYeh, E TKamitani, TBiochem. Biophys. Res. Commun. 251:688-922530630Pubmed1989The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolaseWilkinson, K DLee, K MDeshpande, SDuerksen-Hughes, PBoss, J MPohl, JScience 246:670-316923396Pubmed2006Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memoryGong, BingCao, ZixuanZheng, PingVitolo, Ottavio VLiu, ShuminStaniszewski, AgnieszkaMoolman, DonnaZhang, HongShelanski, MichaelArancio, OttavioCell 126:775-8812210873Pubmed2002ACT and UCH-L1 polymorphisms in Parkinson's disease and age of onsetWang, JianZhao, Chun-YingSi, Yan-MeiLiu, Zhuo-LinChen, BiaoYu, LongMov. Disord. 17:767-71

UCHL3, SENP8 cleave NEDD8

UCHL3 and SENP8 (DEN1) remove the C-terminal extension of NEDD8 propeptides, exposing a C-terminal Gly residue. UCHL3 can also process ubiquitin (Wada et al. 1998). UCHL3 and SENP8 are probably functionally redundant in NEDD8 processing as deletion of either enzyme does not lead to neddylation defects (Chan et al. 2008, Kurihara et al. 2000).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 29356

Reactome DB_ID: 6782635

UCHL3,SENP8:NEDD8(1-88) [cytosol]

UCHL3,SENP8:NEDD8(1-88)

Converted from EntitySet in Reactome

Reactome DB_ID: 5690783

UCHL3,SENP8 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySENP8 [cytosol]UCHL3 [cytosol]

UniProtQ96LD8

Reactome DB_ID: 5690794

UniProt:Q15843 NEDD8

NEDD8

NEDD8FUNCTION Ubiquitin-like protein which plays an important role in cell cycle control and embryogenesis. Covalent attachment to its substrates requires prior activation by the E1 complex UBE1C-APPBP1 and linkage to the E2 enzyme UBE2M. Attachment of NEDD8 to cullins activates their associated E3 ubiquitin ligase activity, and thus promotes polyubiquitination and proteasomal degradation of cyclins and other regulatory proteins.SUBUNIT Directly interacts with NUB1 and AHR. Covalently attached to cullins and p53.TISSUE SPECIFICITY Highly expressed in heart, skeletal muscle, spleen, thymus, prostate, testis, ovary, colon and leukocytes.PTM Cleavage of precursor form by UCHL3 or SENP8 is necessary for function.SIMILARITY Belongs to the ubiquitin family.

UniProtQ15843

EQUAL

Reactome Database ID Release 756782635Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782635ReactomeR-HSA-6782635

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782635.2

Reactome DB_ID: 6782643

UCHL3,SENP8:NEDD8 [cytosol]

UCHL3,SENP8:NEDD8

Converted from EntitySet in Reactome

Reactome DB_ID: 5690783

Reactome DB_ID: 416969

EQUAL

Reactome Database ID Release 756782643Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782643ReactomeR-HSA-6782643

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782643.2

Reactome DB_ID: 6782654

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782635

GO0019784

GO molecular function

Reactome Database ID Release 755690813Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690813Reactome Database ID Release 755690808Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690808ReactomeR-HSA-5690808

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690808.218782863Pubmed2008DEN1 deneddylates non-cullin proteins in vivoChan, YaruYoon, JeongsookWu, June-TaiKim, Hyung-JunPan, Kuan-TingYim, JeongbinChien, Cheng-TingJ. Cell. Sci. 121:3218-2310713173Pubmed2000Expression and functional analysis of Uch-L3 during mouse developmentKurihara, L JSemenova, ELevorse, J MTilghman, S MMol. Cell. Biol. 20:2498-504

UCHL5, USP15 deubiquitinate TGFBR1

Ubiquitin C-terminal hydrolase UCHL5 (UCH37) deubiquitinates TGFBR1, stabilizing TGF-beta receptor complex and prolonging TGF-beta receptor signaling. Deubiqutination of SMAD7 by UCHL5 has not been examined in this context (Wicks et al. 2005). Ubiquitin peptidase USP15 also deubiquitinates and stabilizes TGFBR1, leading to enhanced signaling by TGF-beta receptor complex. USP15 does not affect the ubiquitination status of SMAD7. Amplification of USP15 has recently been reported in glioblastoma, breast and ovarian cancer. In advanced glioblastoma, TGF-beta receptor signaling acts as an oncogenic factor, and USP15-mediated upregulation of TGF-beta receptor signaling may be a key factor in glioblastoma pathogenesis (Eichhorn et al. 2012). The role of UCHL5 was inferred from experiments using recombinant mouse Uchl5 and Smad7 with recombinant human TGF-beta receptors. The role of USP15 was established by experiments using human proteins.

Authored: Orlic-Milacic, M, 2012-04-04Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 2179287

plasma membraneGO0005886TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15 [plasma membrane]

TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15

Reactome DB_ID: 2169047

TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7 [plasma membrane]

TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7

Reactome DB_ID: 173476

TGFB1: p-TGFBR: I-SMAD7 [plasma membrane]

TGFB1: p-TGFBR: I-SMAD7

TGFB1:TGFBR2:p-5S-T185-TGFBR1:I-SMAD7TGF-beta 1:type II receptor:Phospho-type I receptor:I-SMAD7 complex

Reactome DB_ID: 170841

TGFB1:TGFBR2:p-TGFBR1 [plasma membrane]

TGFB1:TGFBR2:p-TGFBR1

TGF-beta 1:type II receptor:Phospho-type I receptor complex

Reactome DB_ID: 170863

p-TGFBR1 [plasma membrane]

p-TGFBR1

Phospho-TGF-beta I receptor complex

Reactome DB_ID: 170849

UniProt:P36897 TGFBR1

TGFBR1

ALK5SKR4TGFBR1FUNCTION Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.ACTIVITY REGULATION Kept in an inactive conformation by FKBP1A preventing receptor activation in absence of ligand. CD109 is another inhibitor of the receptor.SUBUNIT Homodimer; in the endoplasmic reticulum but also at the cell membrane. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric ligands assemble a functional receptor composed of two TGFBR1 and TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The respective affinity of TGBRB1 and TGFBR2 for the ligands may modulate the kinetics of assembly of the receptor and may explain the different biological activities of TGFB1, TGFB2 and TGFB3. Interacts with CD109; inhibits TGF-beta receptor activation in keratinocytes. Interacts with RBPMS. Interacts (unphosphorylated) with FKBP1A; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation. Interacts with SMAD2, SMAD3 and ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta receptor. Interacts with TRAF6 and MAP3K7; induces MAP3K7 activation by TRAF6. Interacts with PARD6A; involved in TGF-beta induced epithelial to mesenchymal transition. Interacts with SMAD7, NEDD4L, SMURF1 and SMURF2; SMAD7 recruits NEDD4L, SMURF1 and SMURF2 to the TGF-beta receptor. Interacts with USP15 and VPS39. Interacts with SDCBP (via C-terminus) (PubMed:25893292) Interacts with CAV1 and this interaction is impaired in the presence of SDCBP (PubMed:25893292). Interacts with APPL1; interaction is TGF beta dependent; mediates trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner (PubMed:26583432).TISSUE SPECIFICITY Found in all tissues examined, most abundant in placenta and least abundant in brain and heart. Expressed in a variety of cancer cell lines (PubMed:25893292).PTM Phosphorylated at basal levels in the absence of ligand. Activated upon phosphorylation by TGFBR2, mainly in the GS domain. Phosphorylation in the GS domain abrogates FKBP1A-binding.PTM N-Glycosylated.PTM Ubiquitinated; undergoes ubiquitination catalyzed by several E3 ubiquitin ligases including SMURF1, SMURF2 and NEDD4L2. Results in the proteasomal and/or lysosomal degradation of the receptor thereby negatively regulating its activity. Deubiquitinated by USP15, leading to stabilization of the protein and enhanced TGF-beta signal. Its ubiquitination and proteasome-mediated degradation is negatively regulated by SDCBP (PubMed:25893292).SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.CAUTION One report originally reported variant Ile-375 (PubMed:22113417). This variant has been subsequently corrected to Arg-375 by the same authors (Ref.49).

UniProtP36897

O-phospho-L-serine at 165

165

EQUAL

O-phospho-L-serine [MOD:00046]

O-phospho-L-threonine at 185

185

EQUAL

O-phospho-L-threonine [MOD:00047]

O-phospho-L-threonine at 186

186

EQUAL

O-phospho-L-serine at 187

187

EQUAL

O-phospho-L-serine at 189

189

EQUAL

O-phospho-L-serine at 191

191

EQUAL

503

EQUAL

Reactome Database ID Release 75170863Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170863ReactomeR-HSA-170863

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170863.1

Reactome DB_ID: 170852

extracellular regionGO0005576Dimeric TGFB1 [extracellular region]

Dimeric TGFB1

Dimeric TGF-beta 1

Reactome DB_ID: 170838

UniProt:P01137 TGFB1

TGFB1

TGFB1TGFBFUNCTION Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.FUNCTION Transforming growth factor beta-1: Multifunctional protein that regulates the growth and differentiation of various cell types and is involved in various processes, such as normal development, immune function, microglia function and responses to neurodegeneration (By similarity). Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains remain non-covalently linked rendering TGF-beta-1 inactive during storage in extracellular matrix (PubMed:29109152). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS that control activation of TGF-beta-1 and maintain it in a latent state during storage in extracellular milieus (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). TGF-beta-1 is released from LAP by integrins (ITGAV:ITGB6 or ITGAV:ITGB8): integrin-binding to LAP stabilizes an alternative conformation of the LAP bowtie tail and results in distortion of the LAP chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Once activated following release of LAP, TGF-beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (PubMed:20207738). While expressed by many cells types, TGF-beta-1 only has a very localized range of action within cell environment thanks to fine regulation of its activation by Latency-associated peptide chain (LAP) and 'milieu molecules' (By similarity). Plays an important role in bone remodeling: acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts (By similarity). Can promote either T-helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner (By similarity). At high concentrations, leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development (By similarity). At low concentrations in concert with IL-6 and IL-21, leads to expression of the IL-17 and IL-23 receptors, favoring differentiation to Th17 cells (By similarity). Stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP) (PubMed:25310401). Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus (PubMed:25893292, PubMed:29483653, PubMed:30696809). Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (PubMed:25893292, PubMed:30696809).SUBUNIT Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Interacts with the serine proteases, HTRA1 and HTRA3: the interaction with either inhibits TGFB1-mediated signaling. The HTRA protease activity is required for this inhibition (By similarity). May interact with THSD4; this interaction may lead to sequestration by FBN1 microfibril assembly and attenuation of TGFB signaling (By similarity). Interacts with CD109, DPT and ASPN (PubMed:9895299, PubMed:16754747, PubMed:17827158). Latency-associated peptide: Homodimer; disulfide-linked (PubMed:28117447, PubMed:29109152). Latency-associated peptide: Interacts with Transforming growth factor beta-1 (TGF-beta-1) chain; interaction is non-covalent and maintains (TGF-beta-1) in a latent state; each Latency-associated peptide (LAP) monomer interacts with TGF-beta-1 in the other monomer (PubMed:29109152). Latency-associated peptide: Interacts with LTBP1; leading to regulate activation of TGF-beta-1 (PubMed:2022183, PubMed:8617200, PubMed:8939931). Latency-associated peptide: Interacts with LRRC32/GARP; leading to regulate activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:22278742, PubMed:19651619). Interacts with LRRC33/NRROS; leading to regulate activation of TGF-beta-1 in macrophages and microglia (Probable). Latency-associated peptide: Interacts (via cell attachment site) with integrins ITGAV and ITGB6 (ITGAV:ITGB6), leading to release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Latency-associated peptide: Interacts with NREP; the interaction results in a decrease in TGFB1 autoinduction (By similarity). Latency-associated peptide: Interacts with HSP90AB1; inhibits latent TGFB1 activation (PubMed:20599762). Transforming growth factor beta-1: Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Transforming growth factor beta-1: Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction (PubMed:20207738).TISSUE SPECIFICITY Highly expressed in bone (PubMed:11746498, PubMed:17827158). Abundantly expressed in articular cartilage and chondrocytes and is increased in osteoarthritis (OA) (PubMed:11746498, PubMed:17827158). Colocalizes with ASPN in chondrocytes within OA lesions of articular cartilage (PubMed:17827158).PTM Transforming growth factor beta-1 proprotein: The precursor proprotein is cleaved in the Golgi apparatus by FURIN to form Transforming growth factor beta-1 (TGF-beta-1) and Latency-associated peptide (LAP) chains, which remain non-covalently linked, rendering TGF-beta-1 inactive.POLYMORPHISM In post-menopausal Japanese women, the frequency of Leu-10 is higher in subjects with osteoporosis than in controls.MISCELLANEOUS TGF-beta-1 is inactivated by fresolimumab (also named GC1008), a monoclonal-neutralizing antibody.SIMILARITY Belongs to the TGF-beta family.

UniProtP01137

279

EQUAL

390

EQUAL

Reactome Database ID Release 75170852Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170852ReactomeR-HSA-170852

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170852.1

Reactome DB_ID: 170866

TGFBR2 homodimer [plasma membrane]

TGFBR2 homodimer

Type II receptor complex

Reactome DB_ID: 170842

UniProt:P37173 TGFBR2

TGFBR2

TGFBR2FUNCTION Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFRB1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways.SUBUNIT Homodimer. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric ligands assemble a functional receptor composed of two TGFBR1 and TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The respective affinity of TGFRB1 and TGFRB2 for the ligands may modulate the kinetics of assembly of the receptor and may explain the different biological activities of TGFB1, TGFB2 and TGFB3. Interacts with DAXX. Interacts with TCTEX1D4. Interacts with ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta receptor. Interacts with and is activated by SCUBE3; this interaction does not affect TGFB1-binding to TGFBR2. Interacts with VPS39; this interaction is independent of the receptor kinase activity and of the presence of TGF-beta. Interacts with CLU (PubMed:8555189).PTM Phosphorylated on a Ser/Thr residue in the cytoplasmic domain.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.

UniProtP37173

EQUAL

567

EQUAL

Reactome Database ID Release 75170866Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170866ReactomeR-HSA-170866

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170866.1Reactome Database ID Release 75170841Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170841ReactomeR-HSA-170841

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170841.1

Reactome DB_ID: 173478

UniProt:O15105 SMAD7

SMAD7

MADH7MADH8SMAD7FUNCTION Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Interacts with WWP1 (By similarity). Interacts with COPS5. Interacts with NEDD4L. Interacts with STAMBP. Interacts with RNF111, AXIN1 and AXIN2. Interacts with PPP1R15A. Interacts (via MH2 domain) with EP300. Interacts with ACVR1B, SMURF1, SMURF2 and TGFBR1; SMAD7 recruits SMURF1 and SMURF2 to the TGF-beta receptor and regulates its degradation. Interacts with PDPK1 (via PH domain).TISSUE SPECIFICITY Ubiquitous with higher expression in the lung and vascular endothelium.INDUCTION By TGFB1.PTM Phosphorylation on Ser-249 does not affect its stability, nuclear localization or inhibitory function in TGFB signaling; however it affects its ability to regulate transcription (By similarity). Phosphorylated by PDPK1.PTM Ubiquitinated by WWP1 (By similarity). Polyubiquitinated by RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation (PubMed:14657019, PubMed:16601693). In response to TGF-beta, ubiquitinated by SMURF1; which promotes its degradation (PubMed:11278251).PTM Acetylation prevents ubiquitination and degradation mediated by SMURF1.SIMILARITY Belongs to the dwarfin/SMAD family.

UniProtO15105

EQUAL

426

EQUAL

Reactome Database ID Release 75173476Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=173476ReactomeR-HSA-173476

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-173476.2Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome Database ID Release 752169047Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2169047ReactomeR-HSA-2169047

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2169047.1Converted from EntitySet in Reactome

Reactome DB_ID: 2179332

UCHL5/USP15 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUCHL5 [cytosol]USP15 [cytosol]

UniProtQ9Y4E8Reactome Database ID Release 752179287Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2179287ReactomeR-HSA-2179287

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2179287.1

Reactome DB_ID: 29356

Reactome DB_ID: 2179328

TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7 [plasma membrane]

TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7

Reactome DB_ID: 173476

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome Database ID Release 752179328Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2179328ReactomeR-HSA-2179328

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2179328.1Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Converted from EntitySet in Reactome

Reactome DB_ID: 2179332

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2179287

Reactome Database ID Release 752179282Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2179282Reactome Database ID Release 752179291Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2179291ReactomeR-HSA-2179291

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2179291.322344298Pubmed2012USP15 stabilizes TGF-? receptor I and promotes oncogenesis through the activation of TGF-? signaling in glioblastomaEichhorn, PJRodón, LGonzàlez-Juncà, ADirac, AGili, MMartínez-Sáez, EAura, CBarba, IPeg, VPrat, ACuartas, IJimenez, JGarcía-Dorado, DSahuquillo, JBernards, RBaselga, JSeoane, JNat Med 18:429-3516027725Pubmed2005The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signallingWicks, SJHaros, KMaillard, MSong, LCohen, REDijke, PTChantry, AOncogene 24:8080-4

Reactome Database ID Release 755689603Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689603ReactomeR-HSA-5689603

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689603.219243136Pubmed2009Polyubiquitin binding and disassembly by deubiquitinating enzymesReyes-Turcu, Francisca EWilkinson, Keith DChem. Rev. 109:1495-50816325574Pubmed2005A genomic and functional inventory of deubiquitinating enzymesNijman, Sebastian M BLuna-Vargas, Mark P AVelds, ArnoBrummelkamp, Thijn RDirac, Annette M GSixma, Titia KBernards, RCell 123:773-86

Ub-specific processing proteases

Ub-specific processing proteases (USPs) are the largest of the DUB families with more than 50 members in humans. The USP catalytic domain varies considerably in size and consists of six conserved motifs with N- or C-terminal extensions and insertions occurring between the conserved motifs (Ye et al. 2009). Two highly conserved regions comprise the catalytic triad, the Cys-box (Cys) and His-box (His and Asp/Asn) (Nijman et al. 2005, Ye et al. 2009, Reyes-Turcu & Wilkinson 2009). They recognize their substrates by interactions of the variable regions with the substrate protein directly, or via scaffolds or adapters in multiprotein complexes.

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

USP7 deubiquitinates TP53,MDM2,MDM4,FOXO4, PTEN

USP7 (HAUSP) is able to deubiquitinate many substrates. It is a key regulator of the tumor suppressor TP53 (p53) (Vousden & Lu 2002). It can act on TP53 directly, or indirectly by acting on the E3 ligase MDM2, which can ubiquitinate TP53 (Chene 2003, Li et al. 2002, 2004, Kon et al. 2010). USP7 also regulates MDM4 (Mdmx), a structural homolog of MDM2 (Meulmeester et al. 2005, Chen 2012). USP7 interacts with and deubiquitinates FOXO4 in response to oxidative stress (van der Horst et al. 2006) and reduces monoubiquitinylation of PTEN, presumably on the previously identified lysine residues 13 and 289 (Trotman et al. 2007), reducing nuclear PTEN levels (Song et al. 2008).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782666

USP7:PolyUb-TP53,PolyUb-MDM2,PolyUb-MDM4,PolyUb-FOXO4,PolyUb-PTEN [nucleoplasm]

USP7:PolyUb-TP53,PolyUb-MDM2,PolyUb-MDM4,PolyUb-FOXO4,PolyUb-PTEN

Converted from EntitySet in Reactome

Reactome DB_ID: 6782516

PolyUb-TP53,PolyUb-MDM2,PolyUb-MDM4,PolyUb-FOXO4,PolyUb-PTEN [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPolyUb-TP53 [nucleoplasm]PolyUb-PTEN [nucleoplasm]PolyUb-FOXO4 [nucleoplasm]PolyUb-MDM2 [nucleoplasm]PolyUb-MDM4 [nucleoplasm]

UniProtP04637UniProtP60484UniProtP98177UniProtQ00987UniProtO15151

Reactome DB_ID: 3215278

UniProt:Q93009 USP7

USP7

USP7HAUSPFUNCTION Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX (PubMed:11923872, PubMed:15053880, PubMed:16964248, PubMed:18716620, PubMed:25283148, PubMed:26678539, PubMed:28655758). Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation (PubMed:15053880, PubMed:16845383, PubMed:18566590, PubMed:20153724). Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53-dependent transcription regulation, cell growth repression and apoptosis (PubMed:25283148). Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis (PubMed:11923872). Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity (PubMed:16964248). In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML (PubMed:18716620). Deubiquitinates KMT2E/MLL5 preventing KMT2E/MLL5 proteasomal-mediated degradation (PubMed:26678539). Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6 (PubMed:22466611, PubMed:22466612). Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1 (PubMed:21745816, PubMed:22411829). Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex (PubMed:20601937). Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo (PubMed:20601937). Exhibits a preference towards 'Lys-48'-linked ubiquitin chains (PubMed:22689415). Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing the transcription factor FOXP3 which is crucial for Treg cell function (PubMed:23973222). Plays a role in the maintenance of the circadian clock periodicity via deubiquitination and stabilization of the CRY1 and CRY2 proteins (PubMed:27123980). Deubiquitinates REST, thereby stabilizing REST and promoting the maintenance of neural progenitor cells (PubMed:21258371). Deubiquitinates SIRT7, inhibiting SIRT7 histone deacetylase activity and regulating gluconeogenesis (PubMed:28655758).FUNCTION (Microbial infection) Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection.ACTIVITY REGULATION Inhibited by N-ethyl-maleimide (NEM) and divalent cations. Tolerates high concentrations of NaCl but is inhibited at concentrations of 195 mM and higher.SUBUNIT Monomer. Homodimer. Part of a complex with DAXX, MDM2, RASSF1 and USP7 (PubMed:18566590). Part of a complex with DAXX, MDM2 and USP7 (PubMed:16845383). Interacts with MDM2; the interaction is independent of p53/TP53. Interacts with DAXX; the interaction is direct and independent of MDM2 and p53/TP53 (PubMed:16845383). Component of a complex composed of KMT2E/MLL5 (isoform 3), OGT (isoform 1) and USP7; the complex stabilizes KMT2E/MLL5, preventing KMT2E/MLL5 ubiquitination and proteosomal-mediated degradation (PubMed:26678539). Interacts (via MATH domain) with KMT2E/MLL5 isoform 3 (PubMed:26678539). Interacts with OGT isoform 1 (PubMed:26678539). Interacts with FOXO4; the interaction is enhanced in presence of hydrogen peroxide and occurs independently of p53/TP53 (PubMed:16964248). Interacts with p53/TP53; the interaction is enhanced in response to DNA damage (PubMed:25283148). Interacts with TSPYL5; this impairs interaction with p53/TP53 (PubMed:21170034). Interacts with PTEN; the interaction is direct (PubMed:18716620). Interacts with ATXN1 and the strength of interaction is influenced by the length of the poly-Gln region in ATXN1 (PubMed:12093161). A weaker interaction seen with mutants having longer poly-Gln regions (PubMed:12093161). Interacts with KIAA1530/UVSSA (PubMed:22466611, PubMed:22466612). Interacts with ABRAXAS2; the interaction is direct (PubMed:25283148). Identified in a complex with TP53/p53 and ABRAXAS2 (PubMed:25283148). Interacts with MEX3C and antagonizes its ability to degrade mRNA (PubMed:22863774). Interacts with DNMT1 and UHRF1 (PubMed:21745816, PubMed:22411829). Interacts with FOXP3 (PubMed:23973222). Interacts (via MATH domain) with RNF220. Associated component of the Polycomb group (PcG) multiprotein PRC1-like complex (PubMed:20601937). Interacts with EPOP (By similarity). Interacts with OTUD4 and USP9X; the interaction is direct (PubMed:25944111). Interacts with CRY2 (PubMed:27123980). Interacts with REST (PubMed:21258371). Interacts with ERCC6 (PubMed:26030138).SUBUNIT (Microbial infection) Isoform 1 and isoform 2 interact with herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 (PubMed:9034339, PubMed:14506283, PubMed:16160161, PubMed:18590780). Binding to ICP0/VMW110 may modulate the substrate specificity or activity of USP7 to stabilize viral proteins.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA1. EBNA1 shows a 10-fold higher affinity than p53/TP53 and can compete with it for USP7 binding.TISSUE SPECIFICITY Expressed in neural progenitor cells (at protein level) (PubMed:21258371). Widely expressed. Overexpressed in prostate cancer.INDUCTION Up-regulated in regulatory T-cells (Treg). Down-regulated during neural progenitor cell differentiation (PubMed:21258371).DOMAIN The C-terminus plays a role in its oligomerization.PTM Isoform 1: Phosphorylated. Isoform 1 is phosphorylated at positions Ser-18 and Ser-963. Isoform 2: Not phosphorylated.PTM Isoform 1: Polyneddylated. Isoform 2: Not Polyneddylated.PTM Isoform 1 and isoform 2: Not sumoylated.PTM Isoform 1 and isoform 2: Polyubiquitinated by herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110; leading to its subsequent proteasomal degradation. Isoform 1: Ubiquitinated at Lys-869.SIMILARITY Belongs to the peptidase C19 family.CAUTION Was reported to interact with UBXN6 but the corresponding article has been retracted (PubMed:18768758).

UniProtQ93009

EQUAL

1102

EQUAL

Reactome Database ID Release 756782666Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782666ReactomeR-HSA-6782666

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782666.2

Reactome DB_ID: 113518

Converted from EntitySet in Reactome

Reactome DB_ID: 6782682

PolyUb [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 6782656

USP7:TP53,MDM2,MDM4,FOXO4,PTEN [nucleoplasm]

USP7:TP53,MDM2,MDM4,FOXO4,PTEN

Converted from EntitySet in Reactome

Reactome DB_ID: 5689977

TP53,MDM2,MDM4,FOXO4,PTEN [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityFOXO4 [nucleoplasm]MDM4 [nucleoplasm]PTEN [nucleoplasm]MDM2 [nucleoplasm]TP53 [nucleoplasm]

Reactome DB_ID: 3215278

EQUAL

1102

EQUAL

Reactome Database ID Release 756782656Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782656ReactomeR-HSA-6782656

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782656.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782666

Reactome Database ID Release 756782631Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782631Reactome Database ID Release 755689950Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689950ReactomeR-HSA-5689950

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689950.211923872Pubmed2002Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilizationLi, MuyangChen, DelinShiloh, ArielLuo, JianyuanNikolaev, Anatoly YQin, JGu, WeiNature 416:648-5315053880Pubmed2004A dynamic role of HAUSP in the p53-Mdm2 pathwayLi, MuyangBrooks, Christopher LKon, NingGu, WeiMol. Cell 13:879-8618716620Pubmed2008The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML networkSong, MSSalmena, LeonardoCarracedo, ArkaitzEgia, AinaraLo-Coco, FTeruya-Feldstein, JuliePandolfi, Pier PaoloNature 455:813-717218261Pubmed2007Ubiquitination regulates PTEN nuclear import and tumor suppressionTrotman, Lloyd CWang, XinjiangAlimonti, AndreaChen, ZhenbangTeruya-Feldstein, JulieYang, HaijuanPavletich, Nikola PCarver, Brett SCordon-Cardo, CarlosErdjument-Bromage, HTempst, PChi, Sung-GilKim, Hyo-JongMisteli, TomJiang, XuejunPandolfi, Pier PaoloCell 128:141-5615916963Pubmed2005Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2Meulmeester, ErikMaurice, Madelon MBoutell, ChrisTeunisse, Amina F A SOvaa, HuibAbraham, Tsion EDirks, Roeland WJochemsen, Aart GMol. Cell 18:565-7612154352Pubmed2002Live or let die: the cell's response to p53Vousden, Karen HLu, XinNat. Rev. Cancer 2:594-60416964248Pubmed2006FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSPvan der Horst, Armandode Vries-Smits, Alida M MBrenkman, Arjan Bvan Triest, Miranda Hvan den Broek, NielsColland, FrédéricMaurice, Madelon MBurgering, BMNat. Cell Biol. 8:1064-7312563309Pubmed2003Inhibiting the p53-MDM2 interaction: an important target for cancer therapyChène, PatrickNat. Rev. Cancer 3:102-923150760Pubmed2012The Roles of MDM2 and MDMX Phosphorylation in Stress Signaling to p53Chen, JiandongGenes Cancer 3:274-8219946331Pubmed2010Inactivation of HAUSP in vivo modulates p53 functionKon, NKobayashi, YLi, MBrooks, C LLudwig, TGu, WOncogene 29:1270-9

USP2 deubiquitinates MDM2,MDM4

The ubiquitin protease USP2 deubiquitinates MDM2 and MDM4 but not TP53 (Stevenson et al. 2007, Allende-Vega et al. 2010).

Authored: Orlic-Milacic, Marija, 2015-10-14Reviewed: Zaccara, Sara, 2016-02-04Reviewed: Inga, Alberto, 2016-02-04Edited: Orlic-Milacic, Marija, 2015-10-14

Reactome DB_ID: 113518

Reactome DB_ID: 6782767

USP2:PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4 [nucleoplasm]

USP2:PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4

USP2:PolyUb-MDM2:PolyUb-MDM4

Reactome DB_ID: 6804937

PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4 [nucleoplasm]

PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4

Reactome DB_ID: 6795669

UniProt:Q00987 MDM2

MDM2

MDM2FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation (PubMed:12821780, PubMed:15053880, PubMed:15195100, PubMed:15632057, PubMed:16337594, PubMed:17290220, PubMed:19098711, PubMed:19219073, PubMed:19837670, PubMed:19965871, PubMed:20173098, PubMed:20385133, PubMed:20858735, PubMed:22128911). Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells (By similarity). Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis (By similarity).SUBUNIT Interacts with p53/TP53, TP73/p73, RBL5 and RP11. Binds specifically to RNA. Can interact with RB1, E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with p53/TP53 and WWOX. Interacts with CDKN2AIP, RFWD3, USP7, PYHIN1, and RBBP6. Interacts with ARRB1 and ARRB2. Interacts with PSMA3. Found in a trimeric complex with MDM2, MDM4 and USP2. Interacts with USP2 (via N-terminus and C-terminus). Interacts with MDM4. Part of a complex with MDM2, DAXX, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7. Interacts directly with DAXX and USP7. Interacts (via C-terminus) with RASSF1 isoform A (via N-terminus); the interaction is independent of TP53. Interacts with APEX1; leading to its ubiquitination and degradation. Interacts with RYBP; this inhibits ubiquitination of TP53. Identified in a complex with RYBP and p53/TP53. Also component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in regulating p53/TP53 stabilization and activity. Binds directly both p53/TP53 and TRIM28. Component of the TRIM28/KAP1-ERBB4-MDM2 complex involved in connecting growth factor responses with DNA damage. Interacts directly with both TRIM28 and ERBB4 in the complex. Interacts with DYRK2. Interacts with IGF1R. Interacts with TRIM13; the interaction ubiquitinates MDM2 leading to its proteasomal degradation. Interacts with SNAI1; this interaction promotes SNAI1 ubiquitination. Interacts with NOTCH1 (via intracellular domain). Interacts with FHIT. Interacts with RFFL and RNF34; the interaction stabilizes MDM2. Interacts with CDK5RAP3 and CDKN2A/ARF; form a ternary complex involved in regulation of p53/TP53 (PubMed:16173922). Interacts with MTA1. Interacts with AARB2. Interacts with MTBP. Interacts with PML. Interacts with TBRG1. Interacts with the 5S RNP which is composed of the 5S RNA, RPL5 and RPL11; the interaction is direct, occurs in the nucleoplasm and negatively regulates MDM2-mediated TP53 ubiquitination and degradation (PubMed:15195100, PubMed:24120868). Interacts with ADGRB1; the interaction results in inhibition of MDM2-mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4 stability and regulating synaptic plasticity (By similarity). Interacts with RPL23A; this interaction may promote p53/TP53 polyubiquitination (PubMed:26203195).SUBUNIT (Microbial infection) Interacts with herpes virus 8 protein v-IRF4.SUBUNIT (Microbial infection) Interacts with and ubiquitinates HIV-1 Tat.TISSUE SPECIFICITY Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues.INDUCTION By DNA damage.DOMAIN Region I is sufficient for binding p53 and inhibiting its G1 arrest and apoptosis functions. It also binds p73 and E2F1. Region II contains most of a central acidic region required for interaction with ribosomal protein L5 and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc interacts specifically with RNA whether or not zinc is present and mediates the heterooligomerization with MDM4. It is also essential for its ubiquitin ligase E3 activity toward p53 and itself.PTM Phosphorylation on Ser-166 by SGK1 activates ubiquitination of p53/TP53. Phosphorylated at multiple sites near the RING domain by ATM upon DNA damage; this prevents oligomerization and E3 ligase processivity and impedes constitutive p53/TP53 degradation.PTM Autoubiquitination leads to proteasomal degradation; resulting in p53/TP53 activation it may be regulated by SFN. Also ubiquitinated by TRIM13. Deubiquitinated by USP2 leads to its accumulation and increases deubiquitination and degradation of p53/TP53. Deubiquitinated by USP7 leading to its stabilization.POLYMORPHISM A polymorphism in the MDM2 promoter is associated with susceptibility to accelerated tumor formation in both hereditary and sporadic cancers [MIM:614401]. It also contributes to susceptibility to Li-Fraumeni syndrome, in patients carrying a TP53 germline mutation.DISEASE Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.MISCELLANEOUS MDM2 RING finger mutations that failed to ubiquitinate p53 in vitro did not target p53 for degradation when expressed in cells.SIMILARITY Belongs to the MDM2/MDM4 family.CAUTION Was reported to interact with UBXN6 but the corresponding article has been retracted (PubMed:18768758).CAUTION A report observed N-glycosylation at Asn-349 (PubMed:19139490). However, as the protein is not extracellular, additional evidence is required to confirm this result.

O-phospho-L-serine at 166

166

EQUAL

O-phospho-L-serine at 188

188

EQUAL

ubiquitinylated lysine (PolyUb [nucleoplasm]) at unknown position

EQUAL

491

EQUAL

Reactome DB_ID: 6804938

UniProt:O15151 MDM4

MDM4

MDMXMDM4FUNCTION Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.SUBUNIT Interacts with MDM2, TP53, TP73 and USP2. Found in a trimeric complex with USP2, MDM2 and MDM4. Interacts (phosphorylated) with YWHAG; negatively regulates MDM4 activity toward TP53.TISSUE SPECIFICITY Expressed in all tissues tested with high levels in thymus.INDUCTION Down-regulated by cisplatin (at protein level).DOMAIN Region I is sufficient for binding TP53 and inhibiting its G1 arrest and apoptosis functions. It also binds TP73. Region II contains most of a central acidic region and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc mediates the heterooligomerization with MDM2.PTM Phosphorylated. Phosphorylation at Ser-367 promotes interaction with YWHAG and subsequent ubiquitination and degradation. Phosphorylation at Ser-342 also induces ubiquitination and degradation but to a lower extent.PTM Ubiquitinated and degraded by MDM2. Deubiquitination by USP2 on the other hand stabilizes the MDM4 protein.SIMILARITY Belongs to the MDM2/MDM4 family.

O-phospho-L-serine at 342

342

EQUAL

O-phospho-L-serine at 367

367

EQUAL

O-phospho-L-serine at 403

403

EQUAL

ubiquitinylated lysine (PolyUb [nucleoplasm]) at unknown position

EQUAL

490

EQUAL

Reactome Database ID Release 756804937Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804937ReactomeR-HSA-6804937

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6804937.1

Reactome DB_ID: 5689946

UniProt:O75604 USP2

USP2

USP2UBP41FUNCTION Hydrolase that deubiquitinates polyubiquitinated target proteins such as MDM2, MDM4 and CCND1 (PubMed:17290220, PubMed:19917254, PubMed:19838211). Isoform 1 and isoform 4 possess both ubiquitin-specific peptidase and isopeptidase activities (By similarity). Deubiquitinates MDM2 without reversing MDM2-mediated p53/TP53 ubiquitination and thus indirectly promotes p53/TP53 degradation and limits p53 activity (PubMed:17290220, PubMed:19838211). Has no deubiquitinase activity against p53/TP53 (PubMed:17290220). Prevents MDM2-mediated degradation of MDM4 (PubMed:17290220). Plays a role in the G1/S cell-cycle progression in normal and cancer cells (PubMed:19917254). Regulates the circadian clock by modulating its intrinsic circadian rhythm and its capacity to respond to external cues (By similarity). Associates with clock proteins and deubiquitinates core clock component PER1 but does not affect its overall stability (By similarity). Regulates the nucleocytoplasmic shuttling and nuclear retention of PER1 and its repressive role on the clock transcription factors CLOCK and ARNTL/BMAL1 (By similarity). Plays a role in the regulation of myogenic differentiation of embryonic muscle cells (By similarity).ACTIVITY REGULATION Cleavage is inhibited by ubiquitin in a dosage-dependent manner. Cleavage is blocked by ubiquitin aldehyde.SUBUNIT Homooligomer (By similarity). Found in trimeric complex with MDM2 and MDM4 and USP2. Interacts with CCND1; the interaction is direct and promotes its stabilization by antagonizing ubiquitin-dependent degradation. Interacts (via N-terminus and C-terminus) with MDM2. Interacts with MDM4. Interacts with PER1 (By similarity). Interacts with KCNQ1; counteracts the NEDD4L-specific down-regulation of I(Ks) and restore plasma membrane localization of KCNQ1 (PubMed:22024150). Isoform 4: Interacts with PDZD3 and CLTC (By similarity).TISSUE SPECIFICITY Expressed in mesangial cells of the kidney and in different types of glomerulonephritides (at protein level).INDUCTION Down-regulated by cisplatin (at protein level).DOMAIN The different N-terminus extensions of isoform 1 and isoform 4 determine their respective subcellular localization and differentiel effect on myoblast fusion and accumulation of muscle-specific proteins. The different N-terminus extensions of isoform 1 and isoform 4 are not essential for their catalytic activity.SIMILARITY Belongs to the peptidase C19 family. USP2 subfamily.

UniProtO75604

EQUAL

605

EQUAL

Reactome Database ID Release 756782767Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782767ReactomeR-HSA-6782767

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782767.1

Reactome DB_ID: 6804936

p-S166,S188-MDM2:p-S346,S367,S403-MDM4 [nucleoplasm]

p-S166,S188-MDM2:p-S346,S367,S403-MDM4

Reactome DB_ID: 6793669

O-phospho-L-serine at 166

166

EQUAL

O-phospho-L-serine at 188

188

EQUAL

491

EQUAL

Reactome DB_ID: 349441

O-phospho-L-serine at 342

342

EQUAL

O-phospho-L-serine at 367

367

EQUAL

O-phospho-L-serine at 403

403

EQUAL

490

EQUAL

Reactome Database ID Release 756804936Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804936ReactomeR-HSA-6804936

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6804936.1

Reactome DB_ID: 5689946

EQUAL

605

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 6782682

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782767

Reactome Database ID Release 755689981Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689981Reactome Database ID Release 755689972Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689972ReactomeR-HSA-5689972

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689972.217290220Pubmed2007The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2Stevenson, Lauren FSparks, AlisonAllende-Vega, NereaXirodimas, Dimitris PLane, David PSaville, Mark KEMBO J. 26:976-8619838211Pubmed2010MdmX is a substrate for the deubiquitinating enzyme USP2aAllende-Vega, NSparks, ALane, D PSaville, M KOncogene 29:432-41

USP10,USP24,USP42 deubiquitinate TP53

USP10 specifically deubiquitinate p53 and not MDM2 (Yuan et al. 2010). USP24 and USP42 also can deubiquitinate p53, regulating the DNA damage response following UV-damage (Hock et al. 2011, Zhang et al. 2015).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 113518

Reactome DB_ID: 6782676

USP10,USP24,USP42:PolyUb-TP53 [nucleoplasm]

USP10,USP24,USP42:PolyUb-TP53

Reactome DB_ID: 6782509

UniProt:P04637 TP53

TP53

TP53P53FUNCTION Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (PubMed:12524540). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (PubMed:12524540). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2 (PubMed:24051492).SUBUNIT Forms homodimers and homotetramers (PubMed:19011621). Binds DNA as a homotetramer. Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1 (By similarity). Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. May interact with HCV core protein. Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity (By similarity). Interacts with ARMC10, BANP, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F1. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-15 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-382) with L3MBTL1. Isoform 1 interacts with isoform 2 and with isoform 4. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with PPIF; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by cyclosporin A (CsA). Interacts with SNAI1; the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts with KAT6A. Interacts with UBC9. Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-binding domain) with ZNF385A; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest. Interacts with ANKRD2. Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination. Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus). Interacts with MORC3 (PubMed:17332504). Interacts (via C-terminus) with POU4F2 isoform 1 (via C-terminus) (PubMed:17145718). Interacts (via oligomerization region) with NOP53; the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of TP53 (PubMed:22522597). Interacts with AFG1L; mediates mitochondrial translocation of TP53 (PubMed:27323408). Interacts with UBD (PubMed:25422469). Interacts with TAF6 isoform 1 and isoform 4 (PubMed:20096117). Interacts with C10orf90/FATS; the interaction inhibits binding of TP53 and MDM2 (By similarity). Interacts with NUPR1; interaction is stress-dependent (PubMed:18690848). Forms a complex with EP300 and NUPR1; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A (PubMed:18690848). Interacts with PRMT5 in response to DNA damage; the interaction is STRAP dependent (PubMed:19011621). Interacts with PPP1R13L (via SH3 domain and ANK repeats); the interaction inhibits pro-apoptotic activity of p53/TP53 (PubMed:12524540). Interacts with PPP1R13B/ASPP1 and TP53BP2/ASPP2; the interactions promotes pro-apoptotic activity (PubMed:12524540). When phosphorylated at Ser-15, interacts with DDX3X and gamma-tubulin (PubMed:28842590). Interacts with KAT7/HBO1; leading to inhibit histone acetyltransferase activity of KAT7/HBO1 (PubMed:17954561).SUBUNIT (Microbial infection) Interacts with cancer-associated/HPV E6 viral proteins leading to ubiquitination and degradation of TP53 giving a possible model for cell growth regulation. This complex formation requires an additional factor, E6-AP, which stably associates with TP53 in the presence of E6.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123.SUBUNIT (Microbial infection) Interacts (via N-terminus) with human adenovirus 5 E1B-55K protein; this interaction leads to the inhibition of TP53 function and/or its degradation.TISSUE SPECIFICITY Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine.INDUCTION Up-regulated in response to DNA damage. Isoform 2 is not induced in tumor cells in response to stress.DOMAIN The nuclear export signal acts as a transcriptional repression domain. The TADI and TADII motifs (residues 17 to 25 and 48 to 56) correspond both to 9aaTAD motifs which are transactivation domains present in a large number of yeast and animal transcription factors.PTM Acetylated. Acetylation of Lys-382 by CREBBP enhances transcriptional activity. Deacetylation of Lys-382 by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence. Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner.PTM Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylated by HIPK1 (By similarity). Phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-18 by VRK1. Phosphorylated on Ser-20 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-20 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Phosphorylated on Thr-55 by TAF1, which promotes MDM2-mediated degradation. Phosphorylated on Ser-33 by CDK7 in a CAK complex in response to DNA damage. Phosphorylated on Ser-46 by HIPK2 upon UV irradiation. Phosphorylation on Ser-46 is required for acetylation by CREBBP. Phosphorylated on Ser-392 following UV but not gamma irradiation. Phosphorylated on Ser-15 upon ultraviolet irradiation; which is enhanced by interaction with BANP. Phosphorylated by NUAK1 at Ser-15 and Ser-392; was initially thought to be mediated by STK11/LKB1 but it was later shown that it is indirect and that STK11/LKB1-dependent phosphorylation is probably mediated by downstream NUAK1 (PubMed:21317932). It is unclear whether AMP directly mediates phosphorylation at Ser-15. Phosphorylated on Thr-18 by isoform 1 and isoform 2 of VRK2. Phosphorylation on Thr-18 by isoform 2 of VRK2 results in a reduction in ubiquitination by MDM2 and an increase in acetylation by EP300. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-15, Ser-33 and Ser-46, leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes. Phosphorylated by DYRK2 at Ser-46 in response to genotoxic stress. Phosphorylated at Ser-315 and Ser-392 by CDK2 in response to DNA-damage. Phosphorylation at Ser-15 is required for interaction with DDX3X and gamma-tubulin (PubMed:28842590).PTM Dephosphorylated by PP2A-PPP2R5C holoenzyme at Thr-55. SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A.PTM May be O-glycosylated in the C-terminal basic region. Studied in EB-1 cell line.PTM Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation (PubMed:10722742, PubMed:12810724, PubMed:15340061, PubMed:17170702, PubMed:19880522). Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:10722742, PubMed:12810724, PubMed:20173098). Ubiquitinated by MKRN1 at Lys-291 and Lys-292, which leads to proteasomal degradation (PubMed:19536131). Deubiquitinated by USP10, leading to its stabilization (PubMed:20096447). Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation (PubMed:19556538). Ubiquitination by TOPORS induces degradation (PubMed:19473992). Deubiquitination by USP7, leading to stabilization (PubMed:15053880). Isoform 4 is monoubiquitinated in an MDM2-independent manner (PubMed:15340061). Ubiquitinated by COP1, which leads to proteasomal degradation (PubMed:19837670). Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2 (PubMed:25732823). Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (By similarity).PTM Monomethylated at Lys-372 by SETD7, leading to stabilization and increased transcriptional activation (PubMed:15525938, PubMed:16415881). Monomethylated at Lys-370 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity (PubMed:17108971). Lys-372 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-370 (PubMed:17108971). Dimethylated at Lys-373 by EHMT1 and EHMT2 (PubMed:20118233). Monomethylated at Lys-382 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity (PubMed:17707234). Dimethylation at Lys-370 and Lys-382 diminishes p53 ubiquitination, through stabilizing association with the methyl reader PHF20 (PubMed:22864287). Demethylation of dimethylated Lys-370 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation (PubMed:17805299). Monomethylated at Arg-333 and dimethylated at Arg-335 and Arg-337 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity (PubMed:19011621).PTM Sumoylated with SUMO1. Sumoylated at Lys-386 by UBC9.DISEASE TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.SIMILARITY Belongs to the p53 family.

ubiquitinylated lysine (PolyUb [cytosol]) at unknown position

EQUAL

393

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 5689984

USP10,USP24,USP42 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUSP24 [nucleoplasm]USP42 [nucleoplasm]USP10 [nucleoplasm]

UniProtQ9UPU5UniProtQ9H9J4UniProtQ14694Reactome Database ID Release 756782676Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782676ReactomeR-HSA-6782676

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782676.2

Reactome DB_ID: 6782788

USP10,USP24,USP42:TP53 [nucleoplasm]

USP10,USP24,USP42:TP53

Converted from EntitySet in Reactome

Reactome DB_ID: 5689984

Reactome DB_ID: 69488

EQUAL

393

EQUAL

Reactome Database ID Release 756782788Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782788ReactomeR-HSA-6782788

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782788.2Converted from EntitySet in Reactome

Reactome DB_ID: 6782682

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782676

Reactome Database ID Release 755689976Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689976Reactome Database ID Release 755689973Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689973ReactomeR-HSA-5689973

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689973.222085928Pubmed2011Regulation of p53 stability and function by the deubiquitinating enzyme USP42Hock, Andreas KVigneron, Arnaud MCarter, StephanieLudwig, Robert LVousden, Karen HEMBO J. 30:4921-3025578727Pubmed2015The deubiquitinating enzyme USP24 is a regulator of the UV damage responseZhang, LNemzow, LeahChen, HLubin, AbigailRong, XiSun, ZhongyiHarris, Thomas KGong, FengCell Rep 10:140-720096447Pubmed2010USP10 regulates p53 localization and stability by deubiquitinating p53Yuan, JianLuo, KuntianZhang, LizhiCheville, John CLou, ZCell 140:384-96

USP3,SAGA deubiquitinate Histone H2A,H2B

USP3 dynamically associates with chromatin and deubiquitinates H2A and H2B in vivo. The ZnF-UBP domain of USP3 mediates the H2A-USP3 interaction (Nicassio et al. 2007). USP22, a component of the hSAGA transcriptional coactivator complex, is able to deubiquitinate Histone H2A and H2B (Zhang et al. 2008, Zhao et al. 2008).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 113518

Reactome DB_ID: 6782792

USP3,SAGA:Ub-histone H2A, Ub-histone H2B [nucleoplasm]

USP3,SAGA:Ub-histone H2A, Ub-histone H2B

Converted from EntitySet in Reactome

Reactome DB_ID: 5690313

USP3, SAGA complex [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUSP3 [nucleoplasm]

UniProtQ9Y6I4Converted from EntitySet in Reactome

Reactome DB_ID: 6782557

Ub-histone H2A, Ub-histone H2B [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 756782792Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782792ReactomeR-HSA-6782792

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782792.2

Reactome DB_ID: 6782785

USP3,SAGA:Histone H2A,Histone H2B [nucleoplasm]

USP3,SAGA:Histone H2A,Histone H2B

Converted from EntitySet in Reactome

Reactome DB_ID: 6782567

Histone H2A,Histone H2B [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Converted from EntitySet in Reactome

Reactome DB_ID: 5690313

Reactome Database ID Release 756782785Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782785ReactomeR-HSA-6782785

Reactome DB_ID: 68524

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782792

Reactome Database ID Release 755690309Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690309Reactome Database ID Release 755690080Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690080ReactomeR-HSA-5690080

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690080.318469533Pubmed2008USP22, an hSAGA subunit and potential cancer stem cell marker, reverses the polycomb-catalyzed ubiquitylation of histone H2AZhang, Xiao-yongPfeiffer, Harla KThorne, Alan WMcMahon, Steven BCell Cycle 7:1522-418206972Pubmed2008A TFTC/STAGA module mediates histone H2A and H2B deubiquitination, coactivates nuclear receptors, and counteracts heterochromatin silencingZhao, YueLang, GuillaumeIto, SayaBonnet, JacquesMetzger, EricSawatsubashi, ShunSuzuki, Erikole Guezennec, XavierStunnenberg, Hendrik GKrasnov, AlekseyGeorgieva, Sofia GSchüle, RolandTakeyama, Ken-IchiKato, ShigeakiTora, LászlóDevys, DidierMol. Cell 29:92-10117980597Pubmed2007Human USP3 is a chromatin modifier required for S phase progression and genome stabilityNicassio, FrancescoCorrado, NadiaVissers, Joseph H AAreces, Liliana BBergink, StevenMarteijn, Jurgen AGeverts, BartHoutsmuller, Adriaan BVermeulen, WimDi Fiore, Pier PaoloCitterio, ElisabettaCurr. Biol. 17:1972-7

USP16,USP21 deubiquitinate Histone H2A

USP16 and USP21 can associate with and deubiquitinate H2A (Joo et al. 2007, Zhang et al. 2014, Nakagawa et al. 2008).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782784

USP16,USP21:Ub-histone H2A [nucleoplasm]

USP16,USP21:Ub-histone H2A

Converted from EntitySet in Reactome

Reactome DB_ID: 6782529

Converted from EntitySet in Reactome

Reactome DB_ID: 5690083

USP16,USP21 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUSP16 [nucleoplasm]USP21 [nucleoplasm]

UniProtQ9Y5T5UniProtQ9UK80Reactome Database ID Release 756782784Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782784ReactomeR-HSA-6782784

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782784.2

Reactome DB_ID: 113518

Converted from EntitySet in Reactome

Reactome DB_ID: 68524

Reactome DB_ID: 6782828

USP16,USP22:Histone H2A [nucleoplasm]

USP16,USP22:Histone H2A

Converted from EntitySet in Reactome

Reactome DB_ID: 4657028

Converted from EntitySet in Reactome

Reactome DB_ID: 5690083

Reactome Database ID Release 756782828Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782828ReactomeR-HSA-6782828

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782828.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782784

Reactome Database ID Release 755690133Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690133Reactome Database ID Release 755690157Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690157ReactomeR-HSA-5690157

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690157.325305019Pubmed2014The histone H2A deubiquitinase USP16 interacts with HERC2 and fine-tunes cellular response to DNA damageZhang, ZhuoYang, HuirongWang, HengbinJ. Biol. Chem. 289:32883-9418172164Pubmed2008Deubiquitylation of histone H2A activates transcriptional initiation via trans-histone cross-talk with H3K4 di- and trimethylationNakagawa, TakeyaKajitani, TakuyaTogo, ShinjiMasuko, NorioOhdan, HidekiHishikawa, YoshitakaKoji, TakehikoMatsuyama, ToshifumiIkura, TsuyoshiMuramatsu, MasamiIto, TakashiGenes Dev. 22:37-4917914355Pubmed2007Regulation of cell cycle progression and gene expression by H2A deubiquitinationJoo, Heui-YunZhai, LingYang, ChunyingNie, ShuyiErdjument-Bromage, HTempst, PChang, ChenbeiWang, HengbinNature 449:1068-72

USP5 cleaves polyubiquitin

USP5 (Isopeptidease T) cleaves linear and branched polyubiquitin (polyUb) with a preference for branched polymers (Wilkonson et al. 1995). It is Involved in the disassembly of unattached lysine-48-linked (K48) polyUb. It also binds linear and K63-linked polyUb with a lower affinity (Dayal et al. 2009).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782783

USP5:PolyUb [cytosol]

USP5:PolyUb

Converted from EntitySet in Reactome

Reactome DB_ID: 5689096

PolyUb [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 5690104

UniProt:P45974 USP5

USP5

USP5ISOTFUNCTION Cleaves linear and branched multiubiquitin polymers with a marked preference for branched polymers. Involved in unanchored 'Lys-48'-linked polyubiquitin disassembly. Binds linear and 'Lys-63'-linked polyubiquitin with a lower affinity. Knock-down of USP5 causes the accumulation of p53/TP53 and an increase in p53/TP53 transcriptional activity because the unanchored polyubiquitin that accumulates is able to compete with ubiquitinated p53/TP53 but not with MDM2 for proteasomal recognition.SUBUNIT Interacts with TRIML1.DOMAIN The UBP-type zinc finger domain interacts selectively with an unmodified C-terminus of the proximal ubiquitin. Both UBA domains are involved in polyubiquitin recognition.MISCELLANEOUS The UBP-type zinc finger domain crystallizes as a dimer linked by a disulfide bond between the Cys-195 residues of both molecules, but there is no evidence that the full-length USP5 exists as a dimer.SIMILARITY Belongs to the peptidase C19 family.

UniProtP45974

EQUAL

858

EQUAL

Reactome Database ID Release 756782783Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782783ReactomeR-HSA-6782783

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782783.2

Reactome DB_ID: 29356

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 6782795

USP5:Ub [cytosol]

USP5:Ub

Reactome DB_ID: 5690104

EQUAL

858

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome Database ID Release 756782795Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782795ReactomeR-HSA-6782795

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782795.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782783

Reactome Database ID Release 755690114Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690114Reactome Database ID Release 755690152Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690152ReactomeR-HSA-5690152

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690152.27578059Pubmed1995Metabolism of the polyubiquitin degradation signal: structure, mechanism, and role of isopeptidase TWilkinson, K DTashayev, V LO'Connor, L BLarsen, C NKasperek, EPickart, C MBiochemistry 34:14535-4619098288Pubmed2009Suppression of the deubiquitinating enzyme USP5 causes the accumulation of unanchored polyubiquitin and the activation of p53Dayal, SaurabhSparks, AlisonJacob, JimmyAllende-Vega, NereaLane, David PSaville, Mark KJ. Biol. Chem. 284:5030-41

USP8 deubiquitinates RNF128

The ubiquitin E3 ligase RNF128 (GRAIL) is regulated by auto-K48-linked ubiquitination, which leads to its proteasomal degradation. RNF128 is bound but not deubiquitinated by OTUB1. USP8 binds the RNF128:OTUB1 complex to remove the ubiquitin attached to GRAIL (Soares et al. 2004, Whiting et al. 2011).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782765

USP8:K48polyUb-RNF128:OTUB1 [cytosol]

USP8:K48polyUb-RNF128:OTUB1

Reactome DB_ID: 6782804

K48polyUb-RNF128:OTUB1 [cytosol]

K48polyUb-RNF128:OTUB1

Reactome DB_ID: 933411

UniProt:Q96FW1 OTUB1

OTUB1

OTB1OTU1HSPC263OTUB1FUNCTION Hydrolase that can specifically remove 'Lys-48'-linked conjugated ubiquitin from proteins and plays an important regulatory role at the level of protein turnover by preventing degradation. Regulator of T-cell anergy, a phenomenon that occurs when T-cells are rendered unresponsive to antigen rechallenge and no longer respond to their cognate antigen. Acts via its interaction with RNF128/GRAIL, a crucial inductor of CD4 T-cell anergy. Isoform 1 destabilizes RNF128, leading to prevent anergy. In contrast, isoform 2 stabilizes RNF128 and promotes anergy. Surprisingly, it regulates RNF128-mediated ubiquitination, but does not deubiquitinate polyubiquitinated RNF128. Deubiquitinates estrogen receptor alpha (ESR1). Mediates deubiquitination of 'Lys-48'-linked polyubiquitin chains, but not 'Lys-63'-linked polyubiquitin chains. Not able to cleave di-ubiquitin. Also capable of removing NEDD8 from NEDD8 conjugates, but with a much lower preference compared to 'Lys-48'-linked ubiquitin.FUNCTION Plays a key non-catalytic role in DNA repair regulation by inhibiting activity of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation of 'Lys-63'-linked histone H2A and H2AX at DNA damage sites. Inhibits RNF168 independently of ubiquitin thioesterase activity by binding and inhibiting UBE2N/UBC13, the E2 partner of RNF168, thereby limiting spreading of 'Lys-63'-linked histone H2A and H2AX marks. Inhibition occurs by binding to free ubiquitin: free ubiquitin acts as an allosteric regulator that increases affinity for UBE2N/UBC13 and disrupts interaction with UBE2V1. The OTUB1-UBE2N/UBC13-free ubiquitin complex adopts a configuration that mimics a cleaved 'Lys48'-linked di-ubiquitin chain.ACTIVITY REGULATION By free ubiquitin: binding of free ubiquitin triggers conformational changes in the OTU domain and formation of a ubiquitin-binding helix in the N-terminus, promoting binding of the conjugated donor ubiquitin in UBE2N/UBC13 to OTUB1.SUBUNIT Isoform 1 and isoform 2 interact with RNF128. Isoform 1 forms a ternary complex with RNF128 and USP8. Isoform 1 interacts with the C-terminal UCH catalytic domain of USP8. Isoform 2 does not associate with USP8. Interacts with FUS, ESR1 and RACK1. Interacts with UBE2N/UBC13.TISSUE SPECIFICITY Isoform 1 is ubiquitous. Isoform 2 is expressed only in lymphoid tissues such as tonsils, lymph nodes and spleen, as well as peripheral blood mononuclear cells.DOMAIN In addition to ubiquitin-binding at the Cys-91 active site, a proximal ubiquitin-binding site is also present at Cys-23 Occupancy of the active site is needed to enable tight binding to the second site. Distinct binding sites for the ubiquitins may allow to discriminate among different isopeptide linkages (i.e. 'Lys-48'-, 'Lys-63'-linked polyubiquitin) in polyubiquitin substrates and achieve linkage-specific deubiquitination.MISCELLANEOUS In the structure described by PubMed:18954305, the His-265 active site of the catalytic triad is located too far to interact directly with the active site Cys-91. A possible explanation is that OTUB1 is in inactive conformation in absence of ubiquitin and a conformation change may move His-265 in the proximity of Cys-91 in presence of ubiquitin substrate.SIMILARITY Belongs to the peptidase C65 family.

UniProtQ96FW1

EQUAL

271

EQUAL

Reactome DB_ID: 6782813

UniProt:Q8TEB7 RNF128

RNF128

RNF128FUNCTION E3 ubiquitin-protein ligase that catalyzes 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains formation. Functions as an inhibitor of cytokine gene transcription. Inhibits IL2 and IL4 transcription, thereby playing an important role in the induction of the anergic phenotype, a long-term stable state of T-lymphocyte unresponsiveness to antigenic stimulation associated with the blockade of interleukin production. Ubiquitinates ARPC5 with 'Lys-48' linkages and COR1A with 'Lys-63' linkages leading to their degradation, down-regulation of these cytosleletal components results in impaired lamellipodium formation and reduced accumulation of F-actin at the immunological synapse. Functions in the patterning of the dorsal ectoderm; sensitizes ectoderm to respond to neural-inducing signals.PATHWAY Protein modification; protein ubiquitination.INDUCTION Induced under anergic conditions. Up-regulated during T-cell anergy induction following signaling through the T-cell antigen receptor.DOMAIN Binding to E2 ubiquitin-conjugating enzyme requires an intact RING finger domain.PTM Auto-ubiquitinated. Controls the development of T-cell clonal anergy by ubiquitination.

UniProtQ8TEB7

ubiquitinylated lysine (K48polyUb [cytosol]) at unknown position

EQUAL

428

EQUAL

Reactome Database ID Release 756782804Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782804ReactomeR-HSA-6782804

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782804.2

Reactome DB_ID: 917720

UniProt:P40818 USP8

USP8

USP8UBPYKIAA0055FUNCTION Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates the stability of STAM2 and RASGRF1. Regulates endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early endosomes, and maintenance of ESCRT-0 stability. The level of protein ubiquitination on endosomes is essential for maintaining the morphology of the organelle. Deubiquitinates EPS15 and controles tyrosine kinase stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. Deubiquitinates BACE1 which inhibits BACE1 lysosomal degradation and modulates BACE-mediated APP cleavage and amyloid-beta formation (PubMed:27302062).SUBUNIT Forms a ternary complex with RNF128 and OTUB1. Interacts (via C-terminal UCH catalytic domain) with OTUB1 isoform 1. Interacts with STAM2 (via SH3 domain). Interacts with DNAJB3, EGFR, EPS15, RASGRF1, RNF41, YWHAE, YWHAG and YWHAZ (By similarity). Interacts with NBR1, RASGRF1, RNF41 and IST1. Associates with the ESCRT-0 complex and with microtubules (By similarity). Interacts with BIRC6/bruce and KIF23/MKLP1.INDUCTION Upon growth stimulation in starved human fibroblasts. Decreases in response to growth arrest induced by cell-cell contact.DOMAIN The MIT domain is required for endosomal localization, CHMP1B-binding, maintenance of ESCRT-0 stability and EGFR degradation.DOMAIN The rhodanese domain is sufficient for RNF41-binding.PTM Phosphorylation of Ser-718 is essential for interaction with YWHAE and for cytosol localization. Undergoes dephosphorylation at Ser-718 in the M phase. Tyrosine-phosphorylated in its N-terminal half in an EGFR-dependent manner.PTM Ubiquitinated. Inactive form is mostly monoubiquitinated, but polyubiquitination happens too. Ubiquitination is increased in EGF-stimulated cells. Ubiquitination of active form is undetectable, suggesting a possibility that USP8 deubiquitinates itself, thereby regulating its own function (By similarity).SIMILARITY Belongs to the peptidase C19 family.

UniProtP40818

EQUAL

1118

EQUAL

Reactome Database ID Release 756782765Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782765ReactomeR-HSA-6782765

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782765.2

Reactome DB_ID: 29356

Reactome DB_ID: 912740

K48polyUb [cytosol]

K48polyUb

Lys-48 polyubiquitinK48-polyubiquitin

Reactome DB_ID: 6782825

USP8:RNF128:OTUB1 [cytosol]

USP8:RNF128:OTUB1

Reactome DB_ID: 6782606

RNF128:OTUB [cytosol]

RNF128:OTUB

Reactome DB_ID: 933411

EQUAL

271

EQUAL

Reactome DB_ID: 5690147

EQUAL

428

EQUAL

Reactome Database ID Release 756782606Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782606ReactomeR-HSA-6782606

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782606.2

Reactome DB_ID: 917720

EQUAL

1118

EQUAL

Reactome Database ID Release 756782825Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782825ReactomeR-HSA-6782825

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782825.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782765

Reactome Database ID Release 756782829Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782829Reactome Database ID Release 755690196Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690196ReactomeR-HSA-5690196

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690196.214661020Pubmed2004Two isoforms of otubain 1 regulate T cell anergy via GRAILSoares, LuisSeroogy, ChristineSkrenta, HeidiAnandasabapathy, NiroshanaLovelace, PatriciaChung, Chan DEngleman, EdgarFathman, C GarrisonNat. Immunol. 5:45-5421078124Pubmed2011GRAIL: a unique mediator of CD4 T-lymphocyte unresponsivenessWhiting, Chan CSu, Leon LLin, Jack TFathman, C GarrisonFEBS J. 278:47-58

USP8 deubiquitinates STAM2:HGS

Monoubiquitination of cell surface receptors is a sorting signal that leads to receptor trafficking from endosomes to lysosomes. Ubiquitinated protein sorting is carried out by class E vacuolar protein sorting (Vps) proteins. Some of these proteins are regulated by monoubiquitination. The Hrs-STAM complex, which is essential for the initial step of the sorting pathway, binds the deubiquitinating enzymes USP8 (UBPY) and STAMBP (AMSH). These bind STAM2 at the same site and may compete for binding (Kato et al. 2000). STAM2 stability is dramatically reduced in USP8 knockdown cells suggesting that its degradation is reduced by the DUB action of USP8 (Row et al. 2006).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782772

USP8:Ub-STAM2:HGS [cytosol]

USP8:Ub-STAM2:HGS

Reactome DB_ID: 6782781

UniProt:O75886 STAM2

STAM2

HBPSTAM2FUNCTION Involved in intracellular signal transduction mediated by cytokines and growth factors. Upon IL-2 and GM-CSL stimulation, it plays a role in signaling leading to DNA synthesis and MYC induction. May also play a role in T-cell development. Involved in down-regulation of receptor tyrosine kinase via multivesicular body (MVBs) when complexed with HGS (ESCRT-0 complex). The ESCRT-0 complex binds ubiquitin and acts as sorting machinery that recognizes ubiquitinated receptors and transfers them to further sequential lysosomal sorting/trafficking processes (By similarity).SUBUNIT Component of the ESCRT-0 complex composed of STAM or STAM2 and HGS. Part of a complex at least composed of HSG, STAM2 and EPS15. Interacts with JAK2 and JAK3. Interacts with ubiquitinated proteins and the deubiquitinating enzyme USP8/UBPY (By similarity). Interacts (via the via the PxVxL motif) with CBX5; the interaction is direct. Interacts with VPS37C. Interacts with ubiquitin; the interaction is direct. Interacts (via UIM domain) with UBQLN1 (via ubiquitin-like domain) (By similarity).TISSUE SPECIFICITY Ubiquitously expressed.DOMAIN The VHS and UIM domains mediate the interaction with ubiquitinated proteins.DOMAIN The SH3 domain mediates the interaction with USP8.DOMAIN Contains one Pro-Xaa-Val-Xaa-Leu (PxVxL) motif, which is required for interaction with chromoshadow domains. This motif requires additional residues -7, -6, +4 and +5 of the central Val which contact the chromoshadow domain.PTM Phosphorylated in response to IL-2, GM-CSF, EGF and PDGF.SIMILARITY Belongs to the STAM family.

UniProtO75886

ubiquitinylated lysine at unknown position

EQUAL

525

EQUAL

Reactome DB_ID: 917720

EQUAL

1118

EQUAL

Reactome DB_ID: 182954

UniProt:O14964 HGS

HGS

HGSHRSFUNCTION Involved in intracellular signal transduction mediated by cytokines and growth factors. When associated with STAM, it suppresses DNA signaling upon stimulation by IL-2 and GM-CSF. Could be a direct effector of PI3-kinase in vesicular pathway via early endosomes and may regulate trafficking to early and late endosomes by recruiting clathrin. May concentrate ubiquitinated receptors within clathrin-coated regions. Involved in down-regulation of receptor tyrosine kinase via multivesicular body (MVBs) when complexed with STAM (ESCRT-0 complex). The ESCRT-0 complex binds ubiquitin and acts as sorting machinery that recognizes ubiquitinated receptors and transfers them to further sequential lysosomal sorting/trafficking processes. May contribute to the efficient recruitment of SMADs to the activin receptor complex. Involved in receptor recycling via its association with the CART complex, a multiprotein complex required for efficient transferrin receptor recycling but not for EGFR degradation.SUBUNIT Component of the ESCRT-0 complex composed of STAM or STAM2 and HGS. Part of a complex at least composed of HSG, STAM2 (or probably STAM) and EPS15 (PubMed:12551915). Interacts with STAM (PubMed:9407053). Interacts with STAM2 (By similarity). Interacts with EPS15; the interaction is direct, calcium-dependent and inhibited by SNAP25 (By similarity). Identified in a complex with STAM and LITAF (PubMed:23166352). Found in a complex with STAM and E3 ligase ITCH and DTX3L (PubMed:24790097). Interacts with E3 ligase DTX3L; the interaction brings together STAM and HSG, promotes their recruitment to early endosomes and decreases STAM and HGS ubiquitination by ITCH (PubMed:24790097). Interacts with NF2; the interaction is direct (PubMed:10861283). Interacts with ubiquitin; the interaction is direct (By similarity). Interacts with VPS37C (PubMed:15509564). Interacts with SMAD1, SMAD2 and SMAD3 (By similarity). Interacts with TSG101; the interaction mediates the association with the ESCRT-I complex (PubMed:21070952). Interacts with SNAP25; the interaction is direct and decreases with addition of increasing concentrations of free calcium (By similarity). Interacts with SNX1; the interaction is direct (By similarity). Component of a 550 kDa membrane complex at least composed of HGS and SNX1 but excluding EGFR (By similarity). Interacts with TRAK1 (PubMed:18675823). Interacts with TRAK2 (By similarity). Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3 (PubMed:15772161). Interacts (via UIM domain) with UBQLN1 (via ubiquitin-like domain) (By similarity). Interacts with ARRDC3 (PubMed:23208550). Identified in a complex containing at least ARRDC4, AVPR2 and HGS (PubMed:23236378). Interacts with LAPTM4B; promotes HGS ubiquitination (PubMed:25588945).TISSUE SPECIFICITY Ubiquitous expression in adult and fetal tissues with higher expression in testis and peripheral blood leukocytes.DOMAIN Has a double-sided UIM that can bind 2 ubiquitin molecules, one on each side of the helix.DOMAIN The FYVE-type zinc finger domain mediates interactions with phosphatidylinositol 3-phosphate in membranes of early endosomes and penetrates bilayers. The FYVE domain insertion into PtdIns(3)P-enriched membranes is substantially increased in acidic conditions.PTM Phosphorylated on Tyr-334. A minor site of phosphorylation on Tyr-329 is detected (By similarity). Phosphorylation occurs in response to EGF, IL-2, GM-CSF and HGF.PTM Ubiquitinated (PubMed:25588945). Ubiquitinated by ITCH (PubMed:14602072, PubMed:24790097).

UniProtO14964

EQUAL

777

EQUAL

Reactome Database ID Release 756782772Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782772ReactomeR-HSA-6782772

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782772.2

Reactome DB_ID: 29356

Reactome DB_ID: 6782796

USP8:STAM2:HGS [cytosol]

USP8:STAM2:HGS

Reactome DB_ID: 917720

EQUAL

1118

EQUAL

Reactome DB_ID: 182965

EQUAL

525

EQUAL

Reactome DB_ID: 182954

EQUAL

777

EQUAL

Reactome Database ID Release 756782796Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782796ReactomeR-HSA-6782796

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782796.2Converted from EntitySet in Reactome

Reactome DB_ID: 113595

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782772

Reactome Database ID Release 756782775Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782775Reactome Database ID Release 756782628Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782628ReactomeR-HSA-6782628

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782628.216520378Pubmed2006The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential for receptor down-regulationRow, Paula EPrior, Ian AMcCullough, JohnClague, Michael JUrbé, SylvieJ. Biol. Chem. 281:12618-2410982817Pubmed2000A deubiquitinating enzyme UBPY interacts with the Src homology 3 domain of Hrs-binding protein via a novel binding motif PX(V/I)(D/N)RXXKPKato, MMiyazawa, KKitamura, NJ. Biol. Chem. 275:37481-7

USP9X (FAM) binds to ubiquitinated SMAD4

In the cytosol, a ubiquitin hydrolase USP9X (FAM) binds to ubiquitinated SMAD4 (Dupont et al. 2009).

Authored: Williams, MG, 2010-06-08Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 870499

UniProt:Q93008 USP9X

USP9X

USP9FAMUSP9XDFFRXFUNCTION Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. May therefore play an important regulatory role at the level of protein turnover by preventing degradation of proteins through the removal of conjugated ubiquitin. Specifically hydrolyzes 'Lys-48'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitins chains. Essential component of TGF-beta/BMP signaling cascade. Specifically deubiquitinates monoubiquitinated SMAD4, opposing the activity of E3 ubiquitin-protein ligase TRIM33. Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Regulates chromosome alignment and segregation in mitosis by regulating the localization of BIRC5/survivin to mitotic centromeres. Involved in axonal growth and neuronal cell migration (PubMed:16322459, PubMed:18254724, PubMed:19135894, PubMed:24607389). Regulates cellular clock function by enhancing the protein stability and transcriptional activity of the core circadian protein ARNTL/BMAL1 via its deubiquitinating activity (PubMed:29626158).SUBUNIT Interacts with SMAD4, MARK4, NUAK1 and BIRC5/survivin. Interacts with DCX. Interacts with OTUD4 and USP7; the interaction is direct (PubMed:25944111). Interacts with ARNTL/BMAL1 (PubMed:29626158).TISSUE SPECIFICITY Widely expressed in embryonic and adult tissues.MISCELLANEOUS Escapes X-inactivation.SIMILARITY Belongs to the peptidase C19 family.

UniProtQ93008

EQUAL

2570

EQUAL

Reactome DB_ID: 870482

Ub-SMAD4 [cytosol]

Ub-SMAD4

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 170862

UniProt:Q13485 SMAD4

SMAD4

SMAD4MADH4DPC4FUNCTION In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Found in a complex with SMAD1 and YY1 (By similarity). Interacts with CITED2 (By similarity). Monomer; in the absence of TGF-beta activation. Heterodimer; on TGF-beta activation. Composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Interacts with ZNF423; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with ZNF521; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Interacts with CITED1. Interacts with PDPK1 (via PH domain) (By similarity). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Interacts with ZC3H3 (By similarity). Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-finger domains) (PubMed:24324267). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts weakly with ZNF8 (PubMed:12370310). Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (PubMed:26878725). Interacts with CREB3L1, the interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator to induce the expression of genes involved in the assembly of collagen extracellular matrix (PubMed:25310401). Interacts with DLX1 (PubMed:14671321). Interacts with ZBTB7A; the interaction is direct and stimulated by TGFB1 (PubMed:25514493). Interacts with CREBBP; the recruitment of this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with EP300; the interaction with this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with HDAC1 (PubMed:25514493). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850).DOMAIN The MH1 domain is required for DNA binding.DOMAIN The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.PTM Phosphorylated by PDPK1.PTM Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling.DISEASE SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.SIMILARITY Belongs to the dwarfin/SMAD family.

UniProtQ13485

EQUAL

552

EQUAL

Reactome Database ID Release 75870482Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=870482ReactomeR-HSA-870482

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-870482.1

Reactome DB_ID: 870520

Ub-SMAD4:USP9X [cytosol]

Ub-SMAD4:USP9X

Reactome DB_ID: 870499

EQUAL

2570

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 170862

EQUAL

552

EQUAL

Reactome Database ID Release 75870520Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=870520ReactomeR-HSA-870520

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-870520.1Reactome Database ID Release 75870479Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=870479ReactomeR-HSA-870479

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-870479.319135894Pubmed2009FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitinationDupont, SMamidi, ACordenonsi, MMontagner, MZacchigna, LAdorno, MMartello, GStinchfield, MJSoligo, SMorsut, LInui, MMoro, SModena, NArgenton, FNewfeld, SJPiccolo, SCell 136:123-35

USP9X (FAM) deubiquitinates SMAD4

USP9X (FAM) deubiquitinates SMAD4, thereby opposing the negative regulatory activity of TRIM33 (Ectodermin) (Dupont et al. 2009).

Authored: Williams, MG, 2010-06-08Reviewed: Huang, Tao, 2012-05-14Edited: Jassal, B, 2012-04-10

Reactome DB_ID: 870520

Reactome DB_ID: 29356

Reactome DB_ID: 870499

EQUAL

2570

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Reactome DB_ID: 170862

EQUAL

552

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 870520

Reactome Database ID Release 75870516Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=870516Reactome Database ID Release 75870437Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=870437ReactomeR-HSA-870437

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-870437.3

ADRM1:26S proteaseome binds USP14

ADRM1 (Rpn13) interacts with the 26S proteasome base unit PRDM1 (Rpn2) via its amino-terminus and is found in the majority of 26S proteasomes. ADRM1 can bind K48-linked di-Ubiquitin (Schreiner et al. 2008, Husnjak et al. 2008) and several de-ubiquitinating enzymes (DUBs) including PSDM14 (Rpn11, POH1), part of the 26S proteasome, and USP14 (Borodovsky et al. 2001, Reyes-Turcu et al. 2009). These proteasome-associated DUBs disassemble poly-Ub chains and recycle ubiquitin during proteasomal degradation. They may also act to prevent the degradation of mis-tagged proteins.

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 5665858

Reactome DB_ID: 5689541

UniProt:P54578 USP14

USP14

TGTUSP14FUNCTION Proteasome-associated deubiquitinase which releases ubiquitin from the proteasome targeted ubiquitinated proteins. Ensures the regeneration of ubiquitin at the proteasome. Is a reversibly associated subunit of the proteasome and a large fraction of proteasome-free protein exists within the cell. Required for the degradation of the chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis. Serves also as a physiological inhibitor of endoplasmic reticulum-associated degradation (ERAD) under the non-stressed condition by inhibiting the degradation of unfolded endoplasmic reticulum proteins via interaction with ERN1. Indispensable for synaptic development and function at neuromuscular junctions (NMJs). Plays a role in the innate immune defense against viruses by stabilizing the viral DNA sensor CGAS and thus inhibiting its autophagic degradation.SUBUNIT Homodimer (Potential). Associates with the 26S proteasome. Interacts with FANCC, CXCR4 and ERN1. Interacts with TRIM14; this interaction recruits USP14 to cleave ubiquitin chains of CGAS.SIMILARITY Belongs to the peptidase C19 family. USP14/UBP6 subfamily.CAUTION Was originally (Ref.1) thought to be a guanine tRNA-ribosyltransferase.

UniProtP54578

EQUAL

494

EQUAL

Reactome DB_ID: 5689592

ADRM1:26S proteasome:USP14 [cytosol]

ADRM1:26S proteasome:USP14

Reactome DB_ID: 5665858

Reactome DB_ID: 5689541

EQUAL

494

EQUAL

Reactome Database ID Release 755689592Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689592ReactomeR-HSA-5689592

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689592.3Reactome Database ID Release 755689539Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5689539ReactomeR-HSA-5689539

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5689539.211566882Pubmed2001A novel active site-directed probe specific for deubiquitylating enzymes reveals proteasome association of USP14Borodovsky, AKessler, B MCasagrande, ROverkleeft, H SWilkinson, K DPloegh, H LEMBO J. 20:5187-96

CYLD mediated deubiquitination of DDX58 (RIG-I)

CYLD is an ovarian tumor (OTU) domain-containing deubiquitinating enzyme (DUB) and has been identified as a negative regulator of DDX58 (RIG-I) mediated antiviral signaling. CYLD associates with the CARD domain of DDX58 and removes K63-linked ubiquitin from the DDX58 CARDs that are conjugated by the E3 ubiquitin ligase, TRIM25 and RNF135.

Authored: Garapati, P V, 2010-08-02Reviewed: Kawai, T, Akira, S, 2010-10-30Edited: Garapati, P V, 2010-08-22

Reactome DB_ID: 918191

UniProt:O95786 DDX58

DDX58

DDX58FUNCTION Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and proinflammatory cytokines. Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments. The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms (PubMed:28469175, PubMed:31006531). Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons (PubMed:28469175, PubMed:31006531). Ligands include 5'-triphosphorylated ssRNAs and dsRNAs but also short dsRNAs (<1 kb in length). In addition to the 5'-triphosphate moiety, blunt-end base pairing at the 5'-end of the RNA is very essential. Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity. A 3'overhang at the 5'triphosphate end decreases and any 5'overhang at the 5' triphosphate end abolishes its activity. Detects both positive and negative strand RNA viruses including members of the families Paramyxoviridae: Human respiratory syncytial virus and measles virus (MeV), Rhabdoviridae: vesicular stomatitis virus (VSV), Orthomyxoviridae: influenza A and B virus, Flaviviridae: Japanese encephalitis virus (JEV), hepatitis C virus (HCV), dengue virus (DENV) and west Nile virus (WNV). It also detects rotaviruses and reoviruses. Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV). Detects dsRNA produced from non-self dsDNA by RNA polymerase III, such as Epstein-Barr virus-encoded RNAs (EBERs). May play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration.SUBUNIT Monomer; maintained as a monomer in an autoinhibited state. Upon binding of viral RNAs and conformational shift, homooligomerizes and forms filaments on these molecules (PubMed:26471729). Interacts (via tandem CARD domain) with MAVS/IPS1 promoting its filamentation. Interacts with DHX58/LGP2, IKBKE, TBK1 and STING1. Interacts (via CARD domain) with TRIM25 (via SPRY domain). Interacts (double-stranded RNA-bound oligomeric form) with RNF135 (homodimer); involved in RNA length-dependent activation of the RIG-I signaling pathway (PubMed:19017631, PubMed:19484123, PubMed:23950712, PubMed:28469175, PubMed:31006531). Interacts with CYLD. Interacts with NLRC5; blocks the interaction of MAVS/IPS1 to DDX58. Interacts with SRC. Interacts with DDX60. Interacts with isoform 2 of ZC3HAV1 (via zinc-fingers) in an RNA-dependent manner. Interacts (via tandem CARD domain) with SEC14L1; the interaction is direct and impairs the interaction of DDX58 with MAVS/IPS1. Interacts with VCP/p97; interaction is direct and allows the recruitment of RNF125 and subsequent ubiquitination and degradation (PubMed:26471729). Interacts with NOP53; may regulate DDX58 through USP15-mediated 'Lys-63'-linked deubiquitination (PubMed:27824081). Interacts with SIGLEC10, CBL and PTPN11; within a negative feedback loop leading to DDX58 degradation (By similarity). Interacts with LRRC25 (PubMed:29288164). Interacts with ZCCHC3; leading to activation of DDX58/RIG-I (PubMed:30193849). Interacts with RNF123 (PubMed:27312109). Interacts with UBE2D3 and UBE2N; E2 ubiquitin ligases involved in RNF135-mediated ubiquitination of DDX58 and activation of the RIG-I signaling pathway (PubMed:28469175). Interacts with IFIT3 (PubMed:21813773). Interacts with DDX3X (PubMed:20127681).SUBUNIT (Microbial infection) Interacts with protein Z of Guanarito virus, Machupo virus, Junin arenavirus and Sabia virus. This interaction disrupts its interaction with MAVS/IPS1, impeding downstream IRF3 and NF-kappa-B activation and resulting in decreased IFN-beta induction (PubMed:20007272).SUBUNIT (Microbial infection) Interacts (via CARD domain) with Human respiratory syncytial virus A non-structural protein 2 (NS2) and this interaction disrupts its interaction with MAVS/IPS1, impeding downstream IRF3 activation (PubMed:19193793).SUBUNIT (Microbial infection) Interacts with Rotavirus A non-structural protein 1 (NSP1) and this interaction induces down-regulation of DDX58/RIG-I (PubMed:22152002).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein US11; this interaction prevents the interaction of MAVS/IPS1 to DDX58 (PubMed:22301138).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL37; this interaction deaminates DDX58 and inhibits its activation.TISSUE SPECIFICITY Present in vascular smooth cells (at protein level).INDUCTION By bacterial lipopolysaccharides (LPS) in endothelial cells. By interferon (IFN).DOMAIN The RLR CTR domain controls homooligomerization and interaction with MAVS/IPS1. In the absence of viral infection, the protein is maintained as a monomer in an autoinhibited state with the CARD domains masked through intramolecular interactions with the RLR CTR domain. Upon binding to viral RNA and ubiquitination by RNF135, a conformational change releases the autoinhibition promoting further homooligomerization, interaction of the CARD domains with the adapter protein MAVS/IPS1 and activation of the downstream RIG-I signaling pathway.DOMAIN The helicase domain is responsible for dsRNA recognition.DOMAIN The 2 CARD domains are responsible for interaction with and signaling through MAVS/IPS1 and for association with the actin cytoskeleton.DOMAIN The second CARD domain is the primary site for 'Lys-63'-linked ubiquitination.PTM (Microbial infection) Deamidated on 'Asn-495' and 'Asn-549' by herpes simplex virus 1 protein UL37. These modifications eliminate DDX58 detection of viral RNA and restriction of viral replication.PTM (Microbial infection) Cleaved by the protease 3C of coxsackievirus B3, poliovirus and enterovirus 71 allowing the virus to disrupt the host type I interferon production.PTM Phosphorylated in resting cells and dephosphorylated in RNA virus-infected cells. Phosphorylation at Thr-770, Ser-854 and Ser-855 results in inhibition of its activity while dephosphorylation at these sites results in its activation.PTM ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN-beta stimulation. ISGylation negatively regulates its function in antiviral signaling response.PTM Sumoylated, probably by MUL1; inhibiting its polyubiquitination.PTM Ubiquitinated. 'Lys-63' ubiquitination by RNF135, which occurs after RNA-binding and homodimerization, releases the autoinhibition of the CARD domains by the RLR CTR domain, an essential step in the activation of the RIG-I signaling pathway (PubMed:23950712, PubMed:28469175, PubMed:31006531). Lys-172 is the critical site of ubiquitination for MAVS/IPS1 binding and to induce anti-viral signal transduction (PubMed:17392790, PubMed:30193849). Lys-154, Lys-164 and Lys-172 are shared sites for RNF135-mediated and TRIM4-mediated ubiquitination (PubMed:19017631, PubMed:19484123, PubMed:24755855). Also undergoes 'Lys-48' ubiquitination at Lys-181 by RNF125 that leads to proteasomal degradation (PubMed:17460044, PubMed:26471729). 'Lys-48' ubiquitination follows viral infection and is enhanced by 'Lys-63'-linked ubiquitination of the CARD domains that promotes interaction with VCP/p97 and subsequent recruitment of RNF125 (PubMed:17460044, PubMed:26471729). Within a negative feedback loop involving SIGLEC10 and PTPN11, 'Lys-48' ubiquitination at Lys-812 by CBL also elicits the proteasomal degradation of DDX58 (By similarity). Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains (PubMed:18636086). Also probably deubiquitinated by USP17L2/USP17 that cleaves 'Lys-48'- and 'Lys-63'-linked ubiquitin chains and positively regulates the receptor (PubMed:20368735).SIMILARITY Belongs to the helicase family. RLR subfamily.

UniProtO95786

ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 154

154

EQUAL

ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 164

164

EQUAL

ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 172

172

EQUAL

925

EQUAL

Reactome DB_ID: 168917

EQUAL

925

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 741420

UniProt:Q9NQC7 CYLD

CYLD

CYLDCYLD1HSPC057KIAA0849FUNCTION Deubiquitinase that specifically cleaves 'Lys-63'- and linear 'Met-1'-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-alpha-induced necroptosis (PubMed:18636086, PubMed:26670046, PubMed:27458237, PubMed:26997266, PubMed:27591049, PubMed:29291351, PubMed:18313383). Plays an important role in the regulation of pathways leading to NF-kappa-B activation (PubMed:12917689, PubMed:12917691). Contributes to the regulation of cell survival, proliferation and differentiation via its effects on NF-kappa-B activation (PubMed:12917690). Negative regulator of Wnt signaling (PubMed:20227366). Inhibits HDAC6 and thereby promotes acetylation of alpha-tubulin and stabilization of microtubules (PubMed:19893491). Plays a role in the regulation of microtubule dynamics, and thereby contributes to the regulation of cell proliferation, cell polarization, cell migration, and angiogenesis (PubMed:18222923, PubMed:20194890). Required for normal cell cycle progress and normal cytokinesis (PubMed:17495026, PubMed:19893491). Inhibits nuclear translocation of NF-kappa-B (PubMed:18636086). Plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation (PubMed:18636086). Dispensable for the maturation of intrathymic natural killer cells, but required for the continued survival of immature natural killer cells (By similarity). Negatively regulates TNFRSF11A signaling and osteoclastogenesis (By similarity). Involved in the regulation of ciliogenesis, allowing ciliary basal bodies to migrate and dock to the plasma membrane; this process does not depend on NF-kappa-B activation (By similarity). Ability to remove linear ('Met-1'-linked) polyubiquitin chains regulates innate immunity and TNF-alpha-induced necroptosis: recruited to the LUBAC complex via interaction with SPATA2 and restricts linear polyubiquitin formation on target proteins (PubMed:26997266, PubMed:26670046, PubMed:27458237, PubMed:27591049). Regulates innate immunity by restricting linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation (PubMed:26997266). Involved in TNF-alpha-induced necroptosis by removing linear ('Met-1'-linked) polyubiquitin chains from RIPK1, thereby regulating the kinase activity of RIPK1 (By similarity). Removes 'Lys-63' linked polyubiquitin chain of MAP3K7, which inhibits phosphorylation and blocks downstream activation of the JNK-p38 kinase cascades (PubMed:29291351).ACTIVITY REGULATION Inhibited by phosphorylation at serine residues.SUBUNIT Interacts (via CAP-Gly domain) with IKBKG/NEMO (via proline-rich C-terminal region) (PubMed:12917689, PubMed:12917690, PubMed:12917691, PubMed:15341735). Interacts with TRAF2 and TRIP (PubMed:12917691, PubMed:14676304). Interacts with PLK1, DVL1, DVL3, MAVS, TBK1, IKKE and DDX58 (PubMed:17495026, PubMed:18636086, PubMed:20227366). Interacts (via CAP-Gly domain) with microtubules (PubMed:19893491). Interacts with HDAC6 and BCL3 (PubMed:19893491). Interacts with MAP3K7 (By similarity). Identified in a complex with TRAF6 and SQSTM1 (By similarity). Interacts with CEP350 (PubMed:25134987). Interacts with RNF31; the interaction is indirect and is mediated via SPATA2 (PubMed:26997266). Interacts with SPATA2 (via the PUB domain); the interaction is direct and recruits CYLD to the LUBAC complex, thereby regulating TNF-alpha-induced necroptosis (PubMed:27307491, PubMed:27458237, PubMed:27545878, PubMed:27591049).TISSUE SPECIFICITY Detected in fetal brain, testis, and skeletal muscle, and at a lower level in adult brain, leukocytes, liver, heart, kidney, spleen, ovary and lung. Isoform 2 is found in all tissues except kidney.PTM Ubiquitinated. Polyubiquitinated in hepatocytes treated with palmitic acid. Ubiquitination is mediated by E3 ligase TRIM47 and leads to proteasomal degradation.PTM Phosphorylated on several serine residues by IKKA and/or IKKB in response to immune stimuli. Phosphorylation requires IKBKG. Phosphorylation abolishes TRAF2 deubiquitination, interferes with the activation of Jun kinases, and strongly reduces CD40-dependent gene activation by NF-kappa-B.SIMILARITY Belongs to the peptidase C19 family.

UniProtQ9NQC7

EQUAL

956

EQUAL

GO0061578

GO molecular function

Reactome Database ID Release 75741421Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=741421Reactome Database ID Release 75936390Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=936390ReactomeR-HSA-936390

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-936390.218467330Pubmed2008Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLDZhang, MWu, XLee, AJJin, WChang, MWright, AImaizumi, TSun, SCJ Biol Chem 283:18621-618636086Pubmed2008The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral responseFriedman, CSO'Donnell, MALegarda-Addison, DNg, ACardenas, Washington BYount, JSMoran, TMBasler, CFKomuro, AHorvath, CMXavier, RTing, ATEMBO Rep 9:930-6

CYLD deubiquitinates K63polyUb-TRAF2,K63polyUb-TRAF6,K63polyUb-RIPK1,K63polyUb-IKBKG

CYLD removes Lys63-linked ubiquitin chains, acting as a negative regulator of NF-kappa-B signaling (Trompouki et al. 2003). It deubiquitinates several NF-kappa-B regulators including TRAF2, TRAF6 (Kovalenko et al. 2003, Trompouki et al. 2003), IKBKG (NEMO) (Brummelkamp et al. 2003), and RIPK1 (Wright et al. 2007).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782801

CYLD:K63polyUb-TRAF2,K63polyUb-TRAF6,K63polyUb-RIPK1,K63polyUb-IKBKG [cytosol]

CYLD:K63polyUb-TRAF2,K63polyUb-TRAF6,K63polyUb-RIPK1,K63polyUb-IKBKG

Converted from EntitySet in Reactome

Reactome DB_ID: 6782771

K63polyUb-TRAF2,K63polyUb-TRAF6,K63polyUb-RIPK1,K63polyUb-IKBKG [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityK63polyUb-NEMO [cytosol]K63polyUb-TRAF2 [cytosol]K63polyUb-RIPK1 [cytosol]K63polyUb-TRAF6 [cytosol]

UniProtQ9Y6K9UniProtQ12933UniProtQ13546UniProtQ9Y4K3

Reactome DB_ID: 741420

EQUAL

956

EQUAL

Reactome Database ID Release 756782801Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782801ReactomeR-HSA-6782801

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782801.2

Reactome DB_ID: 29356

Reactome DB_ID: 450152

K63polyUb [cytosol]

K63polyUb

K63-polyubiquitinLys-63 polyubiquitin

Converted from EntitySet in Reactome

Reactome DB_ID: 6782832

TRAF2,TRAF6,IKBKG,RIPK1 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRIPK1 [cytosol]TRAF2 [cytosol]IKBKG [cytosol]TRAF6 [cytosol]

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782801

Reactome Database ID Release 755696921Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696921Reactome Database ID Release 755696627Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696627ReactomeR-HSA-5696627

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696627.212917689Pubmed2003CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family membersTrompouki, EiriniHatzivassiliou, EudoxiaTsichritzis, TheodoreFarmer, HannahAshworth, AMosialos, GNature 424:793-612917691Pubmed2003The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitinationKovalenko, AChable-Bessia, CCantarella, GIsrael, AWallach, DCourtois, GNature 424:801-517981138Pubmed2007Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLDWright, AtoReiley, William WChang, MikyoungJin, WeiLee, Andrew JoonZhang, MinyingSun, Shao-CongDev. Cell 13:705-1612917690Pubmed2003Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaBBrummelkamp, Thijn RNijman, Sebastian M BDirac, Annette M GBernards, RNature 424:797-801

USP15 deubiquitinates SMAD1,SMAD2,SMAD3, SMAD7:SMURF,KEAP1

USP15 is a ubiquitin-specific protease (Baker et al. 1999) reported to act on several substrates. It promotes deubiquitination of monoubiquitinated R-SMADs, indirectly promoting the activation of TGF-beta target genes (Inui et al. 2011). USP15 binds the SMAD7:SMURF2 complex, deubiquitinating and stabilizing the type I TGFBeta receptor (TGFBR1), leading to enhanced TGF-Beta signalling (Eichorn et al. 2012). USP15 deubiquitinates KEAP1, which suppresses the Nrf2 pathway (Villeneuve et al. 2013).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782777

USP15:Ub-SMAD1,Ub-SMAD2,Ub-SMAD3,Ub-SMAD7:SMURF,Ub-KEAP1 [cytosol]

USP15:Ub-SMAD1,Ub-SMAD2,Ub-SMAD3,Ub-SMAD7:SMURF,Ub-KEAP1

Reactome DB_ID: 2173138

UniProt:Q9Y4E8 USP15

USP15

USP15KIAA0529FUNCTION Hydrolase that removes conjugated ubiquitin from target proteins and regulates various pathways such as the TGF-beta receptor signaling, NF-kappa-B and RNF41/NRDP1-PRKN pathways (PubMed:21947082, PubMed:22344298, PubMed:24852371, PubMed:16005295, PubMed:17318178, PubMed:19826004, PubMed:19576224). Acts as a key regulator of TGF-beta receptor signaling pathway, but the precise mechanism is still unclear: according to a report, acts by promoting deubiquitination of monoubiquitinated R-SMADs (SMAD1, SMAD2 and/or SMAD3), thereby alleviating inhibition of R-SMADs and promoting activation of TGF-beta target genes (PubMed:21947082). According to another reports, regulates the TGF-beta receptor signaling pathway by mediating deubiquitination and stabilization of TGFBR1, leading to an enhanced TGF-beta signal (PubMed:22344298). Able to mediate deubiquitination of monoubiquitinated substrates as well as 'Lys-48'-linked polyubiquitin chains, protecting them against proteasomal degradation. May also regulate gene expression and/or DNA repair through the deubiquitination of histone H2B (PubMed:24526689). Acts as an inhibitor of mitophagy by counteracting the action of parkin (PRKN): hydrolyzes cleavage of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains attached by parkin on target proteins such as MFN2, thereby reducing parkin's ability to drive mitophagy (PubMed:24852371). Acts as an associated component of COP9 signalosome complex (CSN) and regulates different pathways via this association: regulates NF-kappa-B by mediating deubiquitination of NFKBIA and deubiquitinates substrates bound to VCP (PubMed:16005295, PubMed:17318178, PubMed:19826004, PubMed:19576224). Involved in endosome organization by mediating deubiquitination of SQSTM1: ubiquitinated SQSTM1 forms a molecular bridge that restrains cognate vesicles in the perinuclear region and its deubiquitination releases target vesicles for fast transport into the cell periphery (PubMed:27368102).FUNCTION (Microbial infection) Protects APC and human papillomavirus type 16 protein E6 against degradation via the ubiquitin proteasome pathway.SUBUNIT A homodimer structure has been reported; however it is unclear whether the protein form a homodimer in vivo (PubMed:22001210). Identified in a complex with the COP9 signalosome complex (CSN) (PubMed:16005295). Interacts with SMAD1, SMAD2 and SMAD3; the interaction is direct (PubMed:21947082). Forms a complex with SMURF2 and SMAD7 (PubMed:22344298). Interacts with TGFBR1 (PubMed:22344298). Interacts with SART3; the interaction is direct (PubMed:24526689). May interact with RNF20 and RNF40 (PubMed:24526689). May interact with PRKN (PubMed:24852371). Interacts with INCA1 (PubMed:21750715).SUBUNIT (Microbial infection) Interacts with human papillomavirus type 16 protein E6.TISSUE SPECIFICITY Expressed in skeletal muscle, kidney, heart, placenta, liver, thymus, lung, and ovary, with little or no expression in other tissues.PTM Phosphorylated. Phosphorylation protects against ubiquitination and subsequent degradation by the proteasome.PTM Ubiquitinated, leading to degradation by the proteasome.SIMILARITY Belongs to the peptidase C19 family.

EQUAL

981

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 6782776

Ub-SMAD1,Ub-SMAD2,Ub-SMAD3,Ub-SMAD7:SMURF,Ub-KEAP1 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUb-SMAD2 [cytosol]Ub-SMAD1 [cytosol]Ub-KEAP1 [cytosol]Ub-SMAD3 [cytosol]

UniProtQ15796UniProtQ15797UniProtQ14145UniProtP84022Reactome Database ID Release 756782777Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782777ReactomeR-HSA-6782777

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782777.2

Reactome DB_ID: 29356

Reactome DB_ID: 6782802

USP15:SMAD1,SMAD2,SMAD3,KEAP1,SMAD7:SMURF2:TGFBR1 [cytosol]

USP15:SMAD1,SMAD2,SMAD3,KEAP1,SMAD7:SMURF2:TGFBR1

Converted from EntitySet in Reactome

Reactome DB_ID: 6781778

SMAD1,SMAD2,SMAD3,KEAP1,SMAD7:SMURF:TGFBR1 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySMAD1 [cytosol]SMAD2 [cytosol]SMAD3 [cytosol]KEAP1 [cytosol]

Reactome DB_ID: 2173138

EQUAL

981

EQUAL

Reactome Database ID Release 756782802Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782802ReactomeR-HSA-6782802

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782802.2Converted from EntitySet in Reactome

Reactome DB_ID: 113595

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782777

Reactome Database ID Release 756781799Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6781799Reactome Database ID Release 756781764Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6781764ReactomeR-HSA-6781764

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6781764.223727018Pubmed2013USP15 negatively regulates Nrf2 through deubiquitination of Keap1Villeneuve, Nicole FTian, WangWu, TongdeSun, ZhengLau, AlexandriaChapman, EliFang, DeyuZhang, Donna DMol. Cell 51:68-7910444327Pubmed1999Identification, functional characterization, and chromosomal localization of USP15, a novel human ubiquitin-specific protease related to the UNP oncoprotein, and a systematic nomenclature for human ubiquitin-specific proteasesBaker, R TWang, X WWoollatt, EWhite, J ASutherland, G RGenomics 59:264-7421947082Pubmed2011USP15 is a deubiquitylating enzyme for receptor-activated SMADsInui, MasafumiManfrin, AndreaMamidi, AnantMartello, GrazianoMorsut, LeonardoSoligo, SandraEnzo, ElenaMoro, StefanoPolo, SimonaDupont, SirioCordenonsi, MPiccolo, StefanoNat. Cell Biol. 13:1368-75

USP17 deubiquitinates RCE1, CDC25A, DDX58, IFIH1

USP17 regulates cell proliferation by deubiquitinating and inhibiting RCE1, which influences the localization and activation of the small GTPases NRAS and HRAS (Burrows et al. 2009). In addition, USP17 mediates deubiquitination of CDC25A, which prevents CDC25A degradation by the proteasome during the G1/S and G2/M phases, promoting cell-cycle progression (Pereq et al. 2010). USP17 cleaves Lys-48 and Lys-63-linked polyubiquitin chains from the cytoplasmic innate immune receptors DDX58 (RIG-I) and IFIH1 (MDA5), which increases activation of the IFN-beta promoter, part of the cellular response to viral infection (Chen et al. 2010). USP17 expression is upregulated by interleukin-4 and interleukin-6 (Burrows et al. 2004).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782800

USP17:PolyUb-RCE1, PolyUb-CDC25A, PolyUb-DDX58, PolyUb-IFIH1 [cytosol]

USP17:PolyUb-RCE1, PolyUb-CDC25A, PolyUb-DDX58, PolyUb-IFIH1

Converted from EntitySet in Reactome

Reactome DB_ID: 8848677

USP17 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUSP17L2 [cytosol]

UniProtQ6R6M4Converted from EntitySet in Reactome

Reactome DB_ID: 6782764

PolyUb-RCE1, PolyUb-CDC25A, PolyUb-DDX58, PolyUb-IFIH1 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPolyUb-RCE1 [cytosol]PolyUb-CDC25A [cytosol]PolyUb-DDX58 [cytosol]PolyUb-IFIH1 [cytosol]

UniProtQ9Y256UniProtP30304UniProtQ9BYX4Reactome Database ID Release 756782800Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782800ReactomeR-HSA-6782800

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782800.2

Reactome DB_ID: 29356

Reactome DB_ID: 6782822

USP17L1,USP17L2:RCE1, CDC25A, DDX58, IFIH1 [cytosol]

USP17L1,USP17L2:RCE1, CDC25A, DDX58, IFIH1

Converted from EntitySet in Reactome

Reactome DB_ID: 5696897

RCE1, CDC25A, DDX58, IFIH1 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDDX58 [cytosol]IFIH1 [cytosol]CDC25A [cytosol]RCE1 [cytosol]

Converted from EntitySet in Reactome

Reactome DB_ID: 8848677

Reactome Database ID Release 756782822Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782822ReactomeR-HSA-6782822

Reactome DB_ID: 5689096

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782800

Reactome Database ID Release 755696893Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696893Reactome Database ID Release 755696600Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696600ReactomeR-HSA-5696600

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696600.219188362Pubmed2009USP17 regulates Ras activation and cell proliferation by blocking RCE1 activityBurrows, James FKelvin, Alyson AMcFarlane, CherylBurden, Roberta EMcGrattan, Michael JDe la Vega, MichelleGovender, UreshnieQuinn, Derek JDib, KarimGadina, MassimoScott, Christopher JJohnston, James AJ. Biol. Chem. 284:9587-9514699124Pubmed2004DUB-3, a cytokine-inducible deubiquitinating enzyme that blocks proliferationBurrows, James FMcGrattan, Michael JRascle, AnneHumbert, MBaek, Kwang-HyunJohnston, James AJ. Biol. Chem. 279:13993-400020368735Pubmed2010The ubiquitin-specific protease 17 is involved in virus-triggered type I IFN signalingChen, RZhang, LuZhong, BoTan, BoLiu, YuShu, Hong-BingCell Res. 20:802-1120228808Pubmed2010Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25APereg, YaronLiu, Bob YO'Rourke, Karen MSagolla, MeredithDey, AnweshaKomuves, LaszloFrench, Dorothy MDixit, Vishva MNat. Cell Biol. 12:400-6

USP17 deubiquitinates SUDS3

USP17 removes Lys-63-linked ubiquitin chains from SDS3, a key component of the histone deacetylase (HDAC)-dependent Sin3A co-repressor complex, serving to maintain its HDAC activity (Ramakrishna et al. 2011).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 113518

Reactome DB_ID: 6782806

USP17:K63polyUb-SUDS3 [nucleoplasm]

USP17:K63polyUb-SUDS3

Converted from EntitySet in Reactome

Reactome DB_ID: 8848677

Reactome DB_ID: 6782790

UniProt:Q9H7L9 SUDS3

SUDS3

SAP45SDS3SUDS3FUNCTION Regulatory protein which represses transcription and augments histone deacetylase activity of HDAC1. May have a potential role in tumor suppressor pathways through regulation of apoptosis. May function in the assembly and/or enzymatic activity of the mSin3A corepressor complex or in mediating interactions between the complex and other regulatory complexes.SUBUNIT Homodimer. Component of the SIN3 histone deacetylase (HDAC) corepressor complex. Interacts with SIN3A. Interaction with SIN3B enhances the interaction between SIN3B and HDAC1 to form a complex (By similarity). Interacts with HCFC1. Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3/SAP45, ARID4B/SAP180, HDAC1 and HDAC2. Interacts with USP17L2; the interaction is direct. Interacts with FOXK2 (PubMed:25805136).TISSUE SPECIFICITY Expressed in various cancer cell ines.DOMAIN The C-terminus is involved in transcriptional repression by HDAC-independent mechanisms.PTM Polyubiquitinated. 'Lys-63'-polyubiquitinated SUDS3 positively regulates histone deacetylation. Regulated through deubiquitination by USP17L2/USP17 that cleaves 'Lys-63'-linked ubiquitin chains.SIMILARITY Belongs to the SDS3 family.

UniProtQ9H7L9

ubiquitinylated lysine (K63polyUb [nucleoplasm]) at unknown position

EQUAL

328

EQUAL

Reactome Database ID Release 756782806Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782806ReactomeR-HSA-6782806

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782806.2

Reactome DB_ID: 6782513

K63polyUb [nucleoplasm]

K63polyUb

K63-polyubiquitinLys-63 polyubiquitin

Reactome DB_ID: 6782824

USP17:SUDS3 [nucleoplasm]

USP17:SUDS3

Converted from EntitySet in Reactome

Reactome DB_ID: 8848677

Reactome DB_ID: 351696

EQUAL

328

EQUAL

Reactome Database ID Release 756782824Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782824ReactomeR-HSA-6782824

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782824.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782806

Reactome Database ID Release 756783373Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6783373Reactome Database ID Release 756782820Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782820ReactomeR-HSA-6782820

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782820.221239494Pubmed2011Lys-63-specific deubiquitination of SDS3 by USP17 regulates HDAC activityRamakrishna, SureshSuresh, BharathiLee, Eung-JiLee, Hey-JinAhn, Woong-ShickBaek, Kwang-HyunJ. Biol. Chem. 286:10505-14

USP25 deubiquitinates DDX58

USP25, a negative regulator of the virus-triggered type I IFN signaling pathway, cleaves lysine 48- and lysine 63-linked polyubiquitin chains in vitro and in vivo from DDX58 (Retinoic acid-inducible gene I (RIG-I)), Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and TRAF6 to inhibit RIG-I-like receptor-mediated IFN signaling (Zhong et al. 2013).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782844

USP25:PolyUb-DDX58 [cytosol]

USP25:PolyUb-DDX58

Reactome DB_ID: 5696900

UniProt:Q9UHP3 USP25

USP25

USP25USP21FUNCTION Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates and thus, functions to process newly synthesized Ubiquitin, to recycle ubiquitin molecules or to edit polyubiquitin chains and prevents proteasomal degradation of substrates. Hydrolyzes both 'Lys-48'- and 'Lys-63'-linked tetraubiquitin chains.FUNCTION The muscle-specific isoform (USP25m) may have a role in the regulation of muscular differentiation and function.SUBUNIT Homodimer or oligomer. Interacts with ACTA1 (via its C-terminus); the interaction occurs for all isoforms but is strongest for isoform USP25m in muscle differentiating cells. Interacts (isoform USP25m only) with MYBPC1; the interaction prevents proteasomal degradation of MYBPC1. Interacts (isoform USP25m only) with FLNC (via filament repeats 17-18, 20-21 and 24). Interacts with GAPDH. Interacts with SUMO3; the interaction sumoylates efficiently USP25. Interacts with SUMO2; the interaction sumoylates efficiently USP25. Interacts with SUMO1; the interaction only weakly sumoylates USP25. Interacts with SYK; phosphorylates USP25 and regulates USP25 intracellular levels.TISSUE SPECIFICITY Isoform USP25a is found in most adult and fetal tissues; expression is moderately high in testis, pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, but very low in peripheral blood, colon, small intestine, ovary, prostate, thymus and spleen. Isoform USP25b is found in all tissues except heart and skeletal muscle. Isoform USP25m is heart and skeletal muscle specific.INDUCTION The muscle-specific isoform (USP25m) is up-regulated during myocyte differentiation. Levels increase up to 100-fold towards completion of differentiation.PTM Acetylated.PTM Sumoylation impairs binding to and hydrolysis of ubiquitin chains. Sumoylated preferentially with SUMO2 or SUMO3. Desumoylated by SENP1. Regulated by ubiquitination on the same residue.PTM Preferentially monoubiquitinated but can also be polyubiquitinated. Autodeubiquitinated. Ubiquitination activates the enzymatic activity either by preventing sumoylation or by allowing novel interactions.PTM Phosphorylation in the C-terminal by SYK regulates USP25 cellular levels.SIMILARITY Belongs to the peptidase C19 family.

UniProtQ9UHP3

EQUAL

1055

EQUAL

Reactome DB_ID: 6782770

ubiquitinylated lysine (PolyUb [cytosol]) at unknown position

EQUAL

925

EQUAL

Reactome Database ID Release 756782844Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782844ReactomeR-HSA-6782844

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782844.2

Reactome DB_ID: 29356

Converted from EntitySet in Reactome

Reactome DB_ID: 5689096

Reactome DB_ID: 6782841

USP25:DDX58 [cytosol]

USP25:DDX58

Reactome DB_ID: 168917

EQUAL

925

EQUAL

Reactome DB_ID: 5696900

EQUAL

1055

EQUAL

Reactome Database ID Release 756782841Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782841ReactomeR-HSA-6782841

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782841.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782844

Reactome Database ID Release 755696864Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696864Reactome Database ID Release 755696564Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696564ReactomeR-HSA-5696564

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696564.224260525Pubmed2013Ubiquitin-specific proteases 25 negatively regulates virus-induced type I interferon signalingZhong, HuijuanWang, DangFang, LiurongZhang, HuanLuo, RuiShang, MinOuyang, ChaoOuyang, HaipingChen, HuanchunXiao, ShaoboPLoS ONE 8:e80976

USP18 deubiquitinates TAK1:TAB1

Ubiquitination plays a key role in the regulation of signaling via TAK1 (Chen 2012). USP18 catalyzes the deubiquitination of the TAK1:TAB1 complex, reversing TAK1 activating ubiquitination, which restricts activation of NF-kappaB, NFAT and JNK and in decreases the expression of IL2 in T cells after TCR activation (Liu et al. 2013).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782977

USP18:PolyUb-MAP3K7:TAB1 [cytosol]

USP18:PolyUb-MAP3K7:TAB1

Reactome DB_ID: 912325

UniProt:Q9UMW8 USP18

USP18

ISG43USP18FUNCTION Involved in the regulation of inflammatory response to interferon type 1 (PubMed:27325888). Can efficiently cleave only ISG15 fusions including native ISG15 conjugates linked via isopeptide bonds. Necessary to maintain a critical cellular balance of ISG15-conjugated proteins in both healthy and stressed organisms.SIMILARITY Belongs to the peptidase C19 family.

UniProtQ9UMW8

EQUAL

372

EQUAL

Reactome DB_ID: 6782972

PolyUb-MAP3K7:TAB1 [cytosol]

PolyUb-MAP3K7:TAB1

Reactome DB_ID: 167923

UniProt:Q15750 TAB1

TAB1

MAP3K7IP1TAB1FUNCTION May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.SUBUNIT Interacts with XIAP and BIRC7 (PubMed:17560374, PubMed:11865055). Interacts with TRAF6 and MAP3K7; during IL-1 signaling (PubMed:8638164, PubMed:10094049, PubMed:11323434). Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (PubMed:11460167).TISSUE SPECIFICITY Ubiquitous.PTM Monoubiquitinated. Deubiquitinated by Y.enterocolitica YopP.CAUTION Lacks several key residues involved in metal-binding and catalytic activity, therefore has lost phosphatase activity.

UniProtQ15750

EQUAL

504

EQUAL

Reactome DB_ID: 6782968

UniProt:O43318 MAP3K7

MAP3K7

TAK1MAP3K7FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. Phosphorylates RIPK1 at 'Ser-321' which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (By similarity).ACTIVITY REGULATION Activated by proinflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation.SUBUNIT Can form homodimer (PubMed:27426733). Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (PubMed:10838074, PubMed:11460167, PubMed:12242293, PubMed:14670075, PubMed:16289117, PubMed:19675569, PubMed:8638164). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (PubMed:11460167). Interacts with PPM1L and PPM1B/PP2CB (PubMed:11104763). Interaction with PP2A and PPP6C leads to its repressed activity (PubMed:17079228). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (PubMed:10094049, PubMed:12242293). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (PubMed:16893890). Interacts with DYNC2I2 (via WD domains) (PubMed:19521662). Interacts with CYLD and RBCK1 (PubMed:17449468, PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (PubMed:18758450). Interacts with MAPK8IP1 and SMAD6 (By similarity). Interacts with isoform 1 of VRK2 (PubMed:18286207). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (PubMed:15894542). Interacts with TRIM5 (PubMed:21512573). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with PLEKHM1 (via N- and C-terminus) (By similarity). Interacts with TRIM8 (PubMed:22084099). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (By similarity). Interacts with SASH1 (PubMed:23776175). Interacts with RIPK1 (By similarity).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 2 protein US2; this interaction induces MAP3K7 phosphorylation and subsequent activation.TISSUE SPECIFICITY Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form.PTM Association with TAB1/MAP3K7IP1 promotes autophosphorylation at Ser-192 and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Ser-192 by PPM1B/PP2CB and at Thr-187 by PP2A and PPP6C leads to inactivation.PTM 'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation. Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (By similarity). Requires 'Lys-63'-linked polyubiquitination for autophosphorylation and subsequent activation. 'Lys-63'-linked ubiquitination does not lead to proteasomal degradation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains. Deubiquitinated by Y.enterocolitica YopP.PTM (Microbial infection) Cleaved and inactivated by the proteases 3C of coxsackievirus A16 and human enterovirus D68, allowing the virus to disrupt TRAF6-triggered NF-kappa-B induction.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

UniProtO43318

ubiquitinylated lysine (PolyUb [cytosol]) at unknown position

EQUAL

606

EQUAL

Reactome Database ID Release 756782972Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782972ReactomeR-HSA-6782972

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782972.2Reactome Database ID Release 756782977Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782977ReactomeR-HSA-6782977

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782977.2

Reactome DB_ID: 29356

Converted from EntitySet in Reactome

Reactome DB_ID: 5689096

Reactome DB_ID: 6782955

MAP3K7:TAB1 [cytosol]

MAP3K7:TAB1

TAK1:TAB1

Reactome DB_ID: 167923

EQUAL

504

EQUAL

Reactome DB_ID: 168156

EQUAL

606

EQUAL

Reactome Database ID Release 756782955Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782955ReactomeR-HSA-6782955

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782955.2

Reactome DB_ID: 6782967

USP18:MAP3K7:TAB1 [cytosol]

USP18:MAP3K7:TAB1

Reactome DB_ID: 912325

EQUAL

372

EQUAL

Reactome DB_ID: 6782955

Reactome Database ID Release 756782967Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782967ReactomeR-HSA-6782967

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782967.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782977

Reactome Database ID Release 755696923Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696923Reactome Database ID Release 755696534Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696534ReactomeR-HSA-5696534

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696534.222435549Pubmed2012Ubiquitination in signaling to and activation of IKKChen, Zhijian JImmunol. Rev. 246:95-10623825189Pubmed2013USP18 inhibits NF-κB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complexLiu, XikuiLi, HongxiuZhong, BoBlonska, MarzennaGorjestani, SaraYan, MingTian, QiangZhang, Dong-ErLin, XinDong, ChenJ. Exp. Med. 210:1575-90

USP10 deubiquitinates SNX3, CFTR

USP10 deubiquitinates and stabilizes endogenous SNX3 and consequently promotes cell surface expression of ENaC (Boulkroun et al. 2008). USP10 deubiquitinates CFTR in early endosomes thereby enhancing its endocytic recycling (Bomberger et al. 2009).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782985

endosome membraneGO0010008USP10:PolyUb-SNX3,PolyUb-CTFR [endosome membrane]

USP10:PolyUb-SNX3,PolyUb-CTFR

Converted from EntitySet in Reactome

Reactome DB_ID: 6782959

PolyUb-SNX3,PolyUb-CTFR [endosome membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPolyUb-SNX3 [endosome membrane]PolyUb-CFTR [endosome membrane]

UniProtO60493UniProtP13569

Reactome DB_ID: 6782974

UniProt:Q14694 USP10

USP10

KIAA0190USP10FUNCTION Hydrolase that can remove conjugated ubiquitin from target proteins such as p53/TP53, BECN1, SNX3 and CFTR. Acts as an essential regulator of p53/TP53 stability: in unstressed cells, specifically deubiquitinates p53/TP53 in the cytoplasm, leading to counteract MDM2 action and stabilize p53/TP53. Following DNA damage, translocates to the nucleus and deubiquitinates p53/TP53, leading to regulate the p53/TP53-dependent DNA damage response. Component of a regulatory loop that controls autophagy and p53/TP53 levels: mediates deubiquitination of BECN1, a key regulator of autophagy, leading to stabilize the PIK3C3/VPS34-containing complexes. In turn, PIK3C3/VPS34-containing complexes regulate USP10 stability, suggesting the existence of a regulatory system by which PIK3C3/VPS34-containing complexes regulate p53/TP53 protein levels via USP10 and USP13. Does not deubiquitinate MDM2. Deubiquitinates CFTR in early endosomes, enhancing its endocytic recycling. Involved in a TANK-dependent negative feedback response to attenuate NF-kappaB activation via deubiquitinating IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage (PubMed:25861989). Deubiquitinates TBX21 leading to its stabilization (PubMed:24845384).ACTIVITY REGULATION Specifically inhibited by spautin-1 (specific and potent autophagy inhibitor-1), a derivative of MBCQ that binds to USP10 and inhibits deubiquitinase activity. Regulated by PIK3C3/VPS34-containing complexes.SUBUNIT Found in a deubiquitination complex with TANK, USP10 and ZC3H12A; this complex inhibits genotoxic stress- or interleukin-1-beta (IL1B)-mediated NF-kappaB activation by promoting IKBKG or TRAF6 deubiquitination (PubMed:25861989). Interacts with IKBKG; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with TRAF6; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with G3BP1 (via NTF2-like domain) and G3BP2 (via NTF2-like domain) (PubMed:11439350, PubMed:23279204). Interacts with p53/TP53 (PubMed:20096447). Interacts with SNX3 (PubMed:18632802). Interacts with CFTR (PubMed:19398555). Interacts with TBX21 (PubMed:24845384).TISSUE SPECIFICITY Widely expressed.INDUCTION Following DNA damage. Down-regulated in renal cell carcinomas.PTM Phosphorylated by ATM following DNA damage, leading to stablization and translocation it to the nucleus.PTM Ubiquitinated. Deubiquitinated by USP13.SIMILARITY Belongs to the peptidase C19 family. USP10 subfamily.

EQUAL

798

EQUAL

Reactome Database ID Release 756782985Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782985ReactomeR-HSA-6782985

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782985.2

Reactome DB_ID: 29356

Converted from EntitySet in Reactome

Reactome DB_ID: 5689096

Reactome DB_ID: 6782988

USP10:SNX3,CTFR [endosome membrane]

USP10:SNX3,CTFR

Converted from EntitySet in Reactome

Reactome DB_ID: 6782987

SNX3,CTFR [endosome membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityCFTR [endosome membrane]SNX3 [endosome membrane]

Reactome DB_ID: 6782974

EQUAL

798

EQUAL

Reactome Database ID Release 756782988Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782988ReactomeR-HSA-6782988

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782988.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782985

Reactome Database ID Release 756782958Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782958Reactome Database ID Release 756782106Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782106ReactomeR-HSA-6782106

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782106.219398555Pubmed2009The deubiquitinating enzyme USP10 regulates the post-endocytic sorting of cystic fibrosis transmembrane conductance regulator in airway epithelial cellsBomberger, Jennifer MBarnaby, Roxanna LStanton, Bruce AJ. Biol. Chem. 284:18778-8918632802Pubmed2008Vasopressin-inducible ubiquitin-specific protease 10 increases ENaC cell surface expression by deubiquitylating and stabilizing sorting nexin 3Boulkroun, SheerazedRuffieux-Daidié, DorothéeVitagliano, Jean-JacquesPoirot, OlivierCharles, Roch-PhilippeLagnaz, DagmaraFirsov, DmitriKellenberger, StephanStaub, OlivierAm. J. Physiol. Renal Physiol. 295:F889-900

USP12, USP26 deubiquitinate AR

USP12 (as part of a complex with WDR48 and WDR20) and USP26 can bind the androgen receptor and promote its deubiquitination (Faus et al. 2005, Burska et al. 2013, Dirac & Bernards 2010). USP26 is specifically expressed in testis tissue and is a potential infertility gene (Stouffs et al. 2005).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782980

USP12:WDR48:WDR20,USP26:PolyUb-AR [nucleoplasm]

USP12:WDR48:WDR20,USP26:PolyUb-AR

Reactome DB_ID: 6782984

UniProt:P10275 AR

ARNR3C4DHTRFUNCTION Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins like ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024). Transcription activation is also down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.FUNCTION Isoform 3 and isoform 4 lack the C-terminal ligand-binding domain and may therefore constitutively activate the transcription of a specific set of genes independently of steroid hormones.ACTIVITY REGULATION AIM-100 (4-amino-5,6-biaryl-furo[2,3-d]pyrimidine) suppresses TNK2-mediated phosphorylation at Tyr-269. Inhibits the binding of the Tyr-269 phosphorylated form to androgen-responsive enhancers (AREs) and its transcriptional activity.SUBUNIT Binds DNA as a homodimer. Part of a ternary complex containing AR, EFCAB6/DJBP and PARK7. Interacts with HIPK3 and NR0B2 in the presence of androgen. The ligand binding domain interacts with KAT7/HBO1 in the presence of dihydrotestosterone. Interacts with EFCAB6/DJBP, PELP1, PQBP1, RANBP9, RBAK, SPDEF, SRA1, TGFB1I1 and RREB1. Interacts with ZMIZ1/ZIMP10 and ZMIZ2/ZMIP7 which both enhance its transactivation activity. Interacts with SLC30A9 and RAD54L2/ARIP4. Interacts via the ligand-binding domain with LXXLL and FXXLF motifs from NCOA1, NCOA2, NCOA3, NCOA4 and MAGEA11. The AR N-terminal poly-Gln region binds Ran resulting in enhancement of AR-mediated transactivation. Ran-binding decreases as the poly-Gln length increases. Interacts with HIP1 (via coiled coil domain). Interacts (via ligand-binding domain) with TRIM68. Interacts with TNK2. Interacts with USP26. Interacts with RNF6. Interacts (regulated by RNF6 probably through polyubiquitination) with RNF14; regulates AR transcriptional activity. Interacts with PRMT2 and TRIM24. Interacts with RACK1. Interacts with RANBP10; this interaction enhances dihydrotestosterone-induced AR transcriptional activity. Interacts with PRPF6 in a hormone-independent way; this interaction enhances dihydrotestosterone-induced AR transcriptional activity. Interacts with STK4/MST1. Interacts with ZIPK/DAPK3. Interacts with LPXN. Interacts with MAK. Part of a complex containing AR, MAK and NCOA3. Interacts with CRY1. Interacts with CCAR1 and GATA2. Interacts with ZNF318 (By similarity). Interacts with BUD31 (PubMed:25091737). Interacts with ARID4A (PubMed:23487765). Interacts with ARID4B (By similarity). Interacts (via NR LBD domain) with ZBTB7A; the interaction is direct and androgen-dependent (PubMed:20812024). Interacts with NCOR1 (PubMed:20812024). Interacts with NCOR2 (PubMed:20812024). Interacts with CRY2 in a ligand-dependent manner (By similarity).TISSUE SPECIFICITY Isoform 2 is mainly expressed in heart and skeletal muscle (PubMed:15634333). Isoform 3 is expressed by basal and stromal cells of prostate (at protein level) (PubMed:19244107).DOMAIN Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. In the presence of bound steroid the ligand-binding domain interacts with the N-terminal modulating domain, and thereby activates AR transcription factor activity. Agonist binding is required for dimerization and binding to target DNA. The transcription factor activity of the complex formed by ligand-activated AR and DNA is modulated by interactions with coactivator and corepressor proteins (PubMed:25091737). Interaction with RANBP9 is mediated by both the N-terminal domain and the DNA-binding domain. Interaction with EFCAB6/DJBP is mediated by the DNA-binding domain.PTM Sumoylated on Lys-388 (major) and Lys-521. Ubiquitinated. Deubiquitinated by USP26. 'Lys-6' and 'Lys-27'-linked polyubiquitination by RNF6 modulates AR transcriptional activity and specificity.PTM Phosphorylated in prostate cancer cells in response to several growth factors including EGF. Phosphorylation is induced by c-Src kinase (CSK). Tyr-535 is one of the major phosphorylation sites and an increase in phosphorylation and Src kinase activity is associated with prostate cancer progression. Phosphorylation by TNK2 enhances the DNA-binding and transcriptional activity and may be responsible for androgen-independent progression of prostate cancer. Phosphorylation at Ser-83 by CDK9 regulates AR promoter selectivity and cell growth. Phosphorylation by PAK6 leads to AR-mediated transcription inhibition.PTM Palmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid intracellular signaling via ERK and AKT kinases and cAMP generation.POLYMORPHISM The poly-Gln region of AR is highly polymorphic and the number of Gln varies in the population (from 17 to 26). A smaller size of the poly-Gln region may be associated with the development of prostate cancer.POLYMORPHISM The poly-Gly region of AR is polymorphic and ranges from 24 to 31 Gly. A poly-Gly region shorter or equal to 23 may be associated with the development of androgenetic alopecia.DISEASE Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor.MISCELLANEOUS In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity. The hormone-receptor complex appears to recognize discrete DNA sequences upstream of transcriptional start sites.MISCELLANEOUS Transcriptional activity is enhanced by binding to RANBP9.MISCELLANEOUS The level of tyrosine phosphorylation may serve as a diagnostic tool to predict patient outcome in response to hormone-ablation therapy. Inhibition of tyrosine phosphorylation may be an effective intervention target for hormone-refractory prostate cancer.SIMILARITY Belongs to the nuclear hormone receptor family. NR3 subfamily.

UniProtP10275

ubiquitinylated lysine (PolyUb [nucleoplasm]) at unknown position

EQUAL

919

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 5696922

USP12:WDR48:WDR20,USP26 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUSP26 [nucleoplasm]

UniProtQ9BXU7Reactome Database ID Release 756782980Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782980ReactomeR-HSA-6782980

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782980.3

Reactome DB_ID: 113518

Reactome DB_ID: 6782978

USP12:WDR48:WDR20,USP26:AR [nucleoplasm]

USP12:WDR48:WDR20,USP26:AR

Converted from EntitySet in Reactome

Reactome DB_ID: 5696922

Reactome DB_ID: 446174

EQUAL

919

EQUAL

Reactome Database ID Release 756782978Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782978ReactomeR-HSA-6782978

Reactome DB_ID: 6782682

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782980

Reactome Database ID Release 755696924Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696924Reactome Database ID Release 755696605Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696605ReactomeR-HSA-5696605

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696605.220501646Pubmed2010The deubiquitinating enzyme USP26 is a regulator of androgen receptor signalingDirac, Annette M GBernards, RenéMol. Cancer Res. 8:844-5415562280Pubmed2005Possible role of USP26 in patients with severely impaired spermatogenesisStouffs, KatrienLissens, WTournaye, HermanVan Steirteghem, AndréLiebaers, IEur. J. Hum. Genet. 13:336-4024056413Pubmed2013Deubiquitinating enzyme Usp12 is a novel co-activator of the androgen receptorBurska, Urszula LHarle, Victoria JCoffey, KellyDarby, StevenRamsey, HollieO'Neill, DanielLogan, Ian RGaughan, LukeRobson, Craig NJ. Biol. Chem. 288:32641-50

USP11 deubiquitinates NFKBIA

USP11 associates with and deubiquitinates NFKBIA (IkappaBalpha), downregulating TNFalpha-mediated NF-kappaB activation (Sun et al. 2010).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782973

USP11:PolyUb-NFKBIA [cytosol]

USP11:PolyUb-NFKBIA

Reactome DB_ID: 6782960

UniProt:P25963 NFKBIA

NFKBIA

NFKBIAMAD3IKBANFKBIFUNCTION Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL dimers in the cytoplasm through masking of their nuclear localization signals. On cellular stimulation by immune and proinflammatory responses, becomes phosphorylated promoting ubiquitination and degradation, enabling the dimeric RELA to translocate to the nucleus and activate transcription.SUBUNIT Interacts with RELA; the interaction requires the nuclear import signal. Interacts with NKIRAS1 and NKIRAS2. Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Interacts with isoform 1 and isoform 2 of RWDD3; the interaction enhances sumoylation. Interacts (when phosphorylated at the 2 serine residues in the destruction motif D-S-G-X(2,3,4)-S) with BTRC. Associates with the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC; the association is mediated via interaction with BTRC. Part of a SCF(BTRC)-like complex lacking CUL1, which is associated with RELA; RELA interacts directly with NFKBIA. Interacts with PRMT2. Interacts with PRKACA in platelets; this interaction is disrupted by thrombin and collagen. Interacts with HIF1AN. Interacts with MEFV. Interacts with DDRGK1; positively regulates NFKBIA phosphorylation and degradation.SUBUNIT (Microbial infection) Interacts with HBV protein X.INDUCTION Induced in adherent monocytes.PTM Phosphorylated; disables inhibition of NF-kappa-B DNA-binding activity. Phosphorylation at positions 32 and 36 is prerequisite to recognition by UBE2D3 leading to polyubiquitination and subsequent degradation.PTM Sumoylated; sumoylation requires the presence of the nuclear import signal. Sumoylation blocks ubiquitination and proteasome-mediated degradation of the protein thereby increasing the protein stability.PTM Monoubiquitinated at Lys-21 and/or Lys-22 by UBE2D3. Ubiquitin chain elongation is then performed by CDC34 in cooperation with the SCF(FBXW11) E3 ligase complex, building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. The resulting polyubiquitination leads to protein degradation. Also ubiquitinated by SCF(BTRC) following stimulus-dependent phosphorylation at Ser-32 and Ser-36.PTM Deubiquitinated by porcine reproductive and respiratory syndrome virus Nsp2 protein, which thereby interferes with NFKBIA degradation and impairs subsequent NF-kappa-B activation.SIMILARITY Belongs to the NF-kappa-B inhibitor family.

UniProtP25963

ubiquitinylated lysine (PolyUb [cytosol]) at unknown position

EQUAL

317

EQUAL

Reactome DB_ID: 391303

UniProt:P51784 USP11

USP11

USP11UHX1FUNCTION Protease that can remove conjugated ubiquitin from target proteins and polyubiquitin chains (PubMed:12084015, PubMed:15314155, PubMed:17897950, PubMed:19874889, PubMed:20233726, PubMed:24724799). Inhibits the degradation of target proteins by the proteasome (PubMed:12084015). Cleaves preferentially 'Lys-6' and 'Lys-63'-linked ubiquitin chains. Has lower activity with 'Lys-11' and 'Lys-33'-linked ubiquitin chains, and extremely low activity with 'Lys-27', 'Lys-29' and 'Lys-48'-linked ubiquitin chains (in vitro) (PubMed:24724799). Plays a role in the regulation of pathways leading to NF-kappa-B activation (PubMed:17897950, PubMed:19874889). Plays a role in the regulation of DNA repair after double-stranded DNA breaks (PubMed:15314155, PubMed:20233726). Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex (PubMed:20601937).SUBUNIT Monomer (PubMed:24724799). Interacts with RANBP9/RANBPM (PubMed:12084015). Interacts with BRCA2 (PubMed:15314155). Interacts with CHUK/IKKA (PubMed:17897950). Interacts with NFKBIA (PubMed:19874889). Associated component of the Polycomb group (PcG) multiprotein PRC1-like complex (PubMed:20601937).SUBUNIT (Microbial infection) Interacts with papilloma virus protein 16E7 (PubMed:18408009).SIMILARITY Belongs to the peptidase C19 family.CAUTION It is uncertain whether Met-1 or Met-44 is the initiator.

UniProtP51784

EQUAL

963

EQUAL

Reactome Database ID Release 756782973Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782973ReactomeR-HSA-6782973

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782973.2

Reactome DB_ID: 29356

Converted from EntitySet in Reactome

Reactome DB_ID: 5689096

Reactome DB_ID: 6782962

USP11:NFKBIA [cytosol]

USP11:NFKBIA

Reactome DB_ID: 391303

EQUAL

963

EQUAL

Reactome DB_ID: 168151

EQUAL

317

EQUAL

Reactome Database ID Release 756782962Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782962ReactomeR-HSA-6782962

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782962.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782973

Reactome Database ID Release 756781938Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6781938Reactome Database ID Release 756781897Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6781897ReactomeR-HSA-6781897

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6781897.219874889Pubmed2010USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalphaSun, WenjingTan, XiaojieShi, YiXu, GufengMao, RenfangGu, XueFan, YihuiYu, YangBurlingame, SusanZhang, HongRednam, Surya PLu, XiongbinZhang, TingFu, SongbinCao, GuangwenQin, JYang, JianhuaCell. Signal. 22:386-94

USP13 binds SIAH2

USP13 mediates stabilization of the E3-ligase SIAH2 independently of deubiquitinase activity by binding and impairing SIAH2 autoubiquitination (Scortegagna et al. 2011).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6781893

UniProt:Q92995 USP13

USP13

USP13ISOT3FUNCTION Deubiquitinase that mediates deubiquitination of target proteins such as BECN1, MITF, SKP2 and USP10 and is involved in various processes such as autophagy and endoplasmic reticulum-associated degradation (ERAD). Component of a regulatory loop that controls autophagy and p53/TP53 levels: mediates deubiquitination of BECN1, a key regulator of autophagy, leading to stabilize the PIK3C3/VPS34-containing complexes. Also deubiquitinates USP10, an essential regulator of p53/TP53 stability. In turn, PIK3C3/VPS34-containing complexes regulate USP13 stability, suggesting the existence of a regulatory system by which PIK3C3/VPS34-containing complexes regulate p53/TP53 protein levels via USP10 and USP13. Recruited by nuclear UFD1 and mediates deubiquitination of SKP2, thereby regulating endoplasmic reticulum-associated degradation (ERAD). Also regulates ERAD through the deubiquitination of UBL4A a component of the BAG6/BAT3 complex. Mediates stabilization of SIAH2 independently of deubiquitinase activity: binds ubiquitinated SIAH2 and acts by impairing SIAH2 autoubiquitination. Has a weak deubiquitinase activity in vitro and preferentially cleaves 'Lys-63'-linked polyubiquitin chains. In contrast to USP5, it is not able to mediate unanchored polyubiquitin disassembly. Able to cleave ISG15 in vitro; however, additional experiments are required to confirm such data.ACTIVITY REGULATION Specifically inhibited by spautin-1 (specific and potent autophagy inhibitor-1), a derivative of MBCQ that binds to USP13 and inhibits deubiquitinase activity. Regulated by PIK3C3/VPS34-containing complexes. The weak deubiquitinase activity in vitro suggests the existence of some mechanism that activates the enzyme.SUBUNIT Interacts with UFD1. Interacts (via UBA domains) with SIAH2 (when ubiquitinated). Interacts with BAG6; the interaction is direct and may mediate UBL4A deubiquitination (PubMed:24424410). Interacts (via UBA 2 domain) with AMFR; the interaction is direct (PubMed:24424410). Interacts with UBL4A; may be indirect via BAG6 (PubMed:24424410).TISSUE SPECIFICITY Highly expressed in ovary and testes.DOMAIN The UBP-type zinc finger has lost its ability to bind ubiquitin and USP13 is not activated by unanchored ubiquitin. Swapping with the UBP-type zinc finger from USP5 restores ability to bind unanchored ubiquitin and subsequent activation of the protein (PubMed:22216260).DOMAIN The UBA domains mediate binding to ubiquitin.SIMILARITY Belongs to the peptidase C19 family.

UniProtQ92995

EQUAL

863

EQUAL

Reactome DB_ID: 374566

UniProt:O43255 SIAH2

SIAH2

SIAH2FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:9334332, PubMed:11483518, PubMed:19224863). E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:9334332, PubMed:11483518, PubMed:19224863). Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes (PubMed:9334332, PubMed:11483518, PubMed:19224863). Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (GPS2, POU2AF1, PML, NCOR1), a cell surface receptor (DCC), an antiapoptotic protein (BAG1), and a protein involved in synaptic vesicle function in neurons (SYP) (PubMed:9334332, PubMed:11483518, PubMed:19224863). Mediates ubiquitination and proteasomal degradation of DYRK2 in response to hypoxia (PubMed:22878263). It is thereby involved in apoptosis, tumor suppression, cell cycle, transcription and signaling processes (PubMed:9334332, PubMed:11483518, PubMed:19224863, PubMed:22878263). Has some overlapping function with SIAH1 (PubMed:9334332, PubMed:11483518, PubMed:19224863). Triggers the ubiquitin-mediated degradation of TRAF2, whereas SIAH1 does not (PubMed:12411493). Promotes monoubiquitination of SNCA (PubMed:19224863). Regulates cellular clock function via ubiquitination of the circadian transcriptional repressors NR1D1 and NR1D2 leading to their proteasomal degradation (PubMed:26392558). Plays an important role in mediating the rhythmic degradation/clearance of NR1D1 and NR1D2 contributing to their circadian profile of protein abundance (PubMed:26392558). Mediates ubiquitination and degradation of EGLN2 and EGLN3 in response to the unfolded protein response (UPR), leading to their degradation and subsequent stabilization of ATF4 (By similarity).ACTIVITY REGULATION Inhibited by interaction with SNCAIP (isoform 2, but not isoform 1). May be inhibited by interaction with PEG10.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homodimer. Interacts with UBE2E2. Interacts with PEG3 (By similarity). Interacts with VAV1, without mediating its ubiquitin-mediated degradation. Interacts with CACYBP/SIP. Probable component of some large E3 complex possibly composed of UBE2D1, SIAH2, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with PEG10, which may inhibit its activity. Interacts with EGLN2 and SNCAIP. Interacts with DYRK2. Interacts with NR1D1 and NR1D2 (PubMed:26392558). Interacts with DCC (PubMed:9334332).TISSUE SPECIFICITY Widely expressed at low level.DOMAIN The RING-type zinc finger domain is essential for ubiquitin ligase activity.DOMAIN The SBD domain (substrate-binding domain) mediates the homodimerization and the interaction with substrate proteins. It is related to the TRAF family.PTM Phosphorylated at Ser-28 by MAPK14, which mediates the degradation by the proteasome of EGLN3 (By similarity). Phosphorylated at Ser-28 by DYRK2; this increases the ubiquitin ligase activity and promotes degradation of EGLN3.SIMILARITY Belongs to the SINA (Seven in absentia) family.

UniProtO43255

EQUAL

324

EQUAL

Reactome DB_ID: 6782971

SIAH2:USP13 [cytosol]

SIAH2:USP13

Reactome DB_ID: 6781893

EQUAL

863

EQUAL

Reactome DB_ID: 374566

EQUAL

324

EQUAL

Reactome Database ID Release 756782971Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782971ReactomeR-HSA-6782971

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782971.2Reactome Database ID Release 756781899Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6781899ReactomeR-HSA-6781899

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6781899.221659512Pubmed2011USP13 enzyme regulates Siah2 ligase stability and activity via noncatalytic ubiquitin-binding domainsScortegagna, MarziaSubtil, TonyQi, JianfeiKim, HyungsooZhao, WenhuiGu, WeiKluger, HarrietRonai, Ze'ev AJ. Biol. Chem. 286:27333-41

USP13 binds UFD1L:SKP2

In the nucleus USP13 binds UFD1 which acts as a scaffold connecting USP13 to SKP2. USP13 mediates the deubiquitination of SKP2, thereby regulating endoplasmic reticulum-associated degradation (ERAD) by counteracting APC/C(Cdh1)-mediated SKP2 ubiquitination (Chen et al. 2011).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6781888

UFD1L:SKP2 [nucleoplasm]

UFD1L:SKP2

Reactome DB_ID: 5654993

UniProt:Q92890 UFD1

UFD1

UFD1LUFD1FUNCTION Essential component of the ubiquitin-dependent proteolytic pathway which degrades ubiquitin fusion proteins. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. It may be involved in the development of some ectoderm-derived structures (By similarity). Acts as a negative regulator of type I interferon production via the complex formed with VCP and NPLOC4, which binds to DDX58/RIG-I and recruits RNF125 to promote ubiquitination and degradation of DDX58/RIG-I (PubMed:26471729).PATHWAY Protein degradation; proteasomal ubiquitin-dependent pathway.SUBUNIT Heterodimer with NPLOC4, this heterodimer binds VCP and inhibits Golgi membrane fusion (PubMed:11574150, PubMed:26471729). Interacts with USP13 (PubMed:21571647). Interacts with ZFAND2B; probably through VCP (PubMed:24160817).TISSUE SPECIFICITY Found in adult heart, skeletal muscle and pancreas, and in fetal liver and kidney.SIMILARITY Belongs to the UFD1 family.

UniProtQ92890

EQUAL

307

EQUAL

Reactome DB_ID: 975554

UniProt:Q13309 SKP2

SKP2

FBXL1SKP2FUNCTION Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins involved in cell cycle progression, signal transduction and transcription. Specifically recognizes phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. Degradation of CDKN1B/p27kip also requires CKS1. Recognizes target proteins ORC1, CDT1, RBL2, KMT2A/MLL1, CDK9, RAG2, FOXO1, UBP43, and probably MYC, TOB1 and TAL1. Degradation of TAL1 also requires STUB1. Recognizes CDKN1A in association with CCNE1 or CCNE2 and CDK2. Promotes ubiquitination and destruction of CDH1 in a CK1-Dependent Manner, thereby regulating cell migration.FUNCTION Through the ubiquitin-mediated proteasomal degradation of hepatitis C virus non-structural protein 5A, has an antiviral activity towards that virus.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Part of a SCF(SKP2) complex consisting of CUL1, RBX1, SKP1 and SKP2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Interacts directly with CUL1 and SKP1. Interacts with CKS1. Interacts with the cyclin-A-CDK2 complex. Interacts with ORC1, phosphorylated CDT1, phosphorylated RBL2, ELF4, phosphorylated RAG2, FOXO1, UBP43, MYC, TOB1, TAL1 and KMT2A/MLL1. Interacts with TRIM21. Interacts with IFI27; promotes the ubiquitin-mediated proteasomal degradation of NS5A (PubMed:27194766). Interacts with hepatitis C virus/HCV non-structural protein NS5A; promotes the ubiquitin-mediated proteasomal degradation of NS5A (PubMed:27194766).PTM Ubiquitinated by the APC/C complex, leading to its degradation by the proteasome. Deubiquitinated by USP13.PTM Acetylation at Lys-68 and Lys-71 increases stability through impairment of APC/C-mediated proteolysis and promotes cytoplasmic retention. Deacetylated by SIRT3.

UniProtQ13309

EQUAL

424

EQUAL

Reactome Database ID Release 756781888Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6781888ReactomeR-HSA-6781888

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6781888.2

Reactome DB_ID: 6781924

EQUAL

863

EQUAL

Reactome DB_ID: 6781946

USP13:UFD1L:SKP2 [nucleoplasm]

USP13:UFD1L:SKP2

Reactome DB_ID: 6781888

Reactome DB_ID: 6781924

EQUAL

863

EQUAL

Reactome Database ID Release 756781946Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6781946ReactomeR-HSA-6781946

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6781946.3Reactome Database ID Release 756781922Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6781922ReactomeR-HSA-6781922

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6781922.221571647Pubmed2011Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle controlChen, MeifanGutierrez, Gustavo JRonai, Ze'ev AProc. Natl. Acad. Sci. U.S.A. 108:9119-24

USP13 deubiquitinates BECN1,USP10

USP13 preferentially cleaves Lys-63-linked polyubiquitin chains (Zhang et al. 2011). It mediates deubiquitination of BECN1, a key regulator of autophagy, which stabilizes PIK3C3/VPS34-containing complexes. USP13 can deubiquitinate USP10, an essential regulator of TP53 stability (Liu et al. 2011).

Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05

Reactome DB_ID: 6782957

USP13:K63polyUb-BECN1,K63polyUb-USP10 [cytosol]

USP13:K63polyUb-BECN1,K63polyUb-USP10

Reactome DB_ID: 6781893

EQUAL

863

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 6782969

K63polyUb-BECN1,K63polyUb-USP10 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityK63polyUb-USP10 [cytosol]K63polyUb-BECN1 [cytosol]

UniProtQ14457Reactome Database ID Release 756782957Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782957ReactomeR-HSA-6782957

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782957.2

Reactome DB_ID: 29356

Reactome DB_ID: 450152

Reactome DB_ID: 6782992

USP13:BECN1,USP10 [cytosol]

USP13:BECN1,USP10

Converted from EntitySet in Reactome

Reactome DB_ID: 6781894

BECN1,USP10 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityBECN1 [cytosol]USP10 [cytosol]

Reactome DB_ID: 6781893

EQUAL

863

EQUAL

Reactome Database ID Release 756782992Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782992ReactomeR-HSA-6782992

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6782992.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782957

Reactome Database ID Release 756782975Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6782975Reactome Database ID Release 756781779Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6781779ReactomeR-HSA-6781779

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6781779.222216260Pubmed2011Domain analysis reveals that a deubiquitinating enzyme USP13 performs non-activating catalysis for Lys63-linked polyubiquitinZhang, Yu-HangZhou, Chen-JieZhou, Zi-RenSong, Ai-XinHu, Hong-YuPLoS ONE 6:e2936221962518Pubmed2011Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13Liu, JunliXia, HongguangKim, MinsuXu, LihuaLi, YZhang, LihongCai, YuNorberg, Helin VakifahmetogluZhang, TFuruya, TsuyoshiJin, MinzhiZhu, ZhiminWang, HuanchenYu, JiaLi, YanxiaHao, YanChoi, AugustineKe, HengmingMa, DaweiYuan, JunyingCell 147:223-34