BioPAX pathway converted from "UCH proteinases" in the Reactome database.

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: 5665939

cytosolGO0005829

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.

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtQ16186

Chain Coordinates

EQUAL

407

EQUAL

Reactome DB_ID: 68819

26S proteasome [cytosol]

26S proteasome

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 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: 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: 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).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: 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: 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: 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: 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: 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: 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: 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 FAM192A (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 FAM192A (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: 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: 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: 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.

UniProtO75832

EQUAL

226

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: 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: 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: 947610

UniProt:Q8TAA3 PSMA8

PSMA8

PSMA7LPSMA8FUNCTION Component of the spermatoproteasome, a form of the proteasome specifically found in testis that promotes degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. 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 (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 (By similarity). Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SIMILARITY Belongs to the peptidase T1A family.

UniProtQ8TAA3

EQUAL

256

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.

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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.

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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.

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953

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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.

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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).SIMILARITY Belongs to the proteasome subunit S3 family.

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534

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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.

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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.

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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.

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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.

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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.

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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.

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1843

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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.

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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.

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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.

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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.

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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

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300

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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.

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277

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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

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422

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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

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248

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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. 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 PSMD12, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit p55 family.

UniProtO00232

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456

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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).SIMILARITY Belongs to the AAA ATPase family.

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406

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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.

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440

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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

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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

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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

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Reactome Database ID Release 7068819Database 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: 5665858

ADRM1:26S proteasome [cytosol]

ADRM1:26S proteasome

Reactome DB_ID: 5665939

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Reactome DB_ID: 68819

Reactome Database ID Release 705665858Database 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 705665871Database 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-5665871.218497827Pubmed2008Ubiquitin docking at the proteasome through a novel pleckstrin-homology domain interactionSchreiner, PatrickChen, XiangHusnjak, KoraljkaRandles, LeahZhang, NaixiaElsasser, SuzanneFinley, DanielDikic, IvanWalters, Kylie JGroll, MichaelNature 453:548-5218497817Pubmed2008Proteasome subunit Rpn13 is a novel ubiquitin receptorHusnjak, KoraljkaElsasser, SuzanneZhang, NaixiaChen, XiangRandles, LeahShi, YuanHofmann, KayWalters, Kylie JFinley, DanielDikic, IvanNature 453:481-819489724Pubmed2009Regulation 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.

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Reactome DB_ID: 5665858

Reactome DB_ID: 5665845

ADRM1:26S proteasome:UCHL5 [cytosol]

ADRM1:26S proteasome:UCHL5

Reactome DB_ID: 1629778

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Reactome DB_ID: 5665858

Reactome Database ID Release 705665845Database 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 705665854Database 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. 25:5742-5324752541Pubmed2014Mechanism 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 385:737-4016990800Pubmed2006A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomesHamazaki, JunIemura, SNatsume, TYashiroda, HidekiTanaka, KeijiMurata, ShigeoEMBO J. 25:4524-36

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

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Reactome DB_ID: 5689568

INO80 complex [nucleoplasm]

INO80 complex

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

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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

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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

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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

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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

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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.FUNCTION 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. 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. 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. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AFZ from the nucleosome.FUNCTION Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.FUNCTION Plays an essential role in oncogenic transformation by MYC and also modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex. Essential for cell proliferation.FUNCTION May be able to bind plasminogen at cell surface and enhance plasminogen activation.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).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

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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 Actin, cytoplasmic 1, N-terminally processed: N-terminal acetylation by NAA80 affects actin filament depolymerization and elongation, including elongation driven by formins (PubMed:29581253). In contrast, filament nucleation by the Arp2/3 complex is not affected (PubMed:29581253).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

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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

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607

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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

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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

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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

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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

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414

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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

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462

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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

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1299

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Reactome Database ID Release 705689568Database 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

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Reactome DB_ID: 5689568

Reactome Database ID Release 705689602Database 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 705689544Database 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-5689544.218922472Pubmed2008Distinct 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. 8:994-100219062292Pubmed2009The INO80 chromatin remodeling complex in transcription, replication and repairConaway, Ronald CConaway, Joan WelikyTrends Biochem. Sci. 34:71-7

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: 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 PhysicalEntityFOXK2 [nucleoplasm]FOXK1 [nucleoplasm]

UniProtQ01167UniProtP85037Converted 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: 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). Part of a complex composed at least of ASCL2, EMSY, HCFC1, HSPA8, CCAR2, MATR3, MKI67, RBBP5, TUBB2A, WDR5 and ZNF335; this complex may have a histone H3-specific methyltransferase activity (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

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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).FUNCTION Isoform 2: the mitochondrial isoform (mOGT) is cytotoxic and triggers apoptosis in several cell types including INS1, an insulinoma cell line.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 Database ID Release 705689678Database 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 705689653Database 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: 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: 5689682

BAP1:BAP1-interacting complex [nucleoplasm]

BAP1:BAP1-interacting complex

Reactome DB_ID: 5689653

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome Database ID Release 705689682Database 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 705689630Database 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-5689630.219682612Pubmed2010Control of alpha-herpesvirus IE gene expression by HCF-1 coupled chromatin modification activitiesKristie, Thomas MLiang, YVogel, Jodi LBiochim. Biophys. Acta 1799:257-6519117993Pubmed2009BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activityNishikawa, HiroyukiWu, WenwenKoike, AyakaKojima, RyokoGomi, HiromichiFukuda, MamoruOhta, TomohikoCancer Res. 69:111-923277170Pubmed2013Tumours associated with BAP1 mutationsMurali, RajmohanWiesner, ThomasScolyer, Richard APathology 45:116-2620805357Pubmed2010The 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. 30:5071-859528852Pubmed1998BAP1: 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 16:1097-11219188440Pubmed2009Association 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. 284:34179-88

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: 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: 5689665

EQUAL

729

EQUAL

Reactome DB_ID: 5690771

BAP1:BARD1 [nucleoplasm]

BAP1:BARD1

Reactome DB_ID: 5659775

EQUAL

777

EQUAL

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome Database ID Release 705690771Database 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 705689649Database 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: 5690821

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

1807

EQUAL

ubiquitinylated lysine [MOD:01148]

EQUAL

2035

EQUAL

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome DB_ID: 5690760

BAP1:K48polyUb,K63polyUb-HCFC1 [nucleoplasm]

BAP1:K48polyUb,K63polyUb-HCFC1

Reactome DB_ID: 5690821

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

1807

EQUAL

2035

EQUAL

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome Database ID Release 705690760Database 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 705690785Database 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

3.4.19.12

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: 5690760

Reactome DB_ID: 113518

water [ChEBI:15377]

water

ChEBI15377Converted 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

Reactome DB_ID: 5690817

BAP1:HCFC1 [nucleoplasm]

BAP1:HCFC1

Reactome DB_ID: 1592209

EQUAL

2035

EQUAL

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome Database ID Release 705690817Database 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-5690817.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 5690760

GO0036459

GO molecular function

Reactome Database ID Release 705690780Database 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 705690759Database 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

3.4.19.12

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

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

Reactome DB_ID: 113518

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 PhysicalEntityUBC(381-456) [nucleoplasm]UBB(1-76) [nucleoplasm]UBC(305-380) [nucleoplasm]UBC(229-304) [nucleoplasm]UBC(609-684) [nucleoplasm]UBB(153-228) [nucleoplasm]UBA52(1-76) [nucleoplasm]UBC(77-152) [nucleoplasm]UBC(1-76) [nucleoplasm]UBC(153-228) [nucleoplasm]RPS27A(1-76) [nucleoplasm]UBB(77-152) [nucleoplasm]UBC(457-532) [nucleoplasm]UBC(533-608) [nucleoplasm]

UniProtP0CG48UniProtP0CG47UniProtP62987UniProtP62979Converted 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

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 5690807

PR-DUB complex [nucleoplasm]

PR-DUB complex

Reactome DB_ID: 5690793

PR-DUB core complex [nucleoplasm]

PR-DUB core complex

Converted from EntitySet in Reactome

Reactome DB_ID: 5689640

Reactome DB_ID: 5689665

EQUAL

729

EQUAL

Reactome Database ID Release 705690793Database 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: 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: 1592209

EQUAL

2035

EQUAL

Converted from EntitySet in Reactome

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]

UniProtQ9P267UniProtQ96DN6Reactome Database ID Release 705690807Database 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 705690792Database 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 705690790Database 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-5690790.324634419Pubmed2014MBD5 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 14:2179-8922878500Pubmed2012Loss 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 337:1541-620436459Pubmed2010Histone 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 465:243-7

3.4.19.12

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: 6782633

UCHL1,UCHL3:Ub-Lys [cytosol]

UCHL1,UCHL3:Ub-Lys

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]

UniProtP09936UniProtP15374Converted 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-UBB(153-228) [cytosol]N6-glycyl-L-lysine-UBC(381-456) [cytosol]N6-glycyl-L-lysine-UBA52(1-76) [cytosol]N6-glycyl-L-lysine-UBC(305-380) [cytosol]N6-glycyl-L-lysine-UBC(609-684) [cytosol]N6-glycyl-L-lysine-RPS27A(1-76) [cytosol]N6-glycyl-L-lysine-UBC(1-76) [cytosol]N6-glycyl-L-lysine-UBB(1-76) [cytosol]N6-glycyl-L-lysine-UBB(77-152) [cytosol]N6-glycyl-L-lysine-UBC(229-304) [cytosol]N6-glycyl-L-lysine-UBC(77-152) [cytosol]N6-glycyl-L-lysine-UBC(533-608) [cytosol]N6-glycyl-L-lysine-UBC(153-228) [cytosol]N6-glycyl-L-lysine-UBC(457-532) [cytosol]

Reactome Database ID Release 706782633Database 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: 29356

Reactome DB_ID: 6782592

UCHL1,UCHL3:Ub [cytosol]

UCHL1,UCHL3:Ub

Converted from EntitySet in Reactome

Reactome DB_ID: 5690768

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 PhysicalEntityUBA52(1-76) [cytosol]UBC(1-76) [cytosol]UBC(457-532) [cytosol]UBC(609-684) [cytosol]UBB(1-76) [cytosol]RPS27A(1-76) [cytosol]UBC(381-456) [cytosol]UBC(305-380) [cytosol]UBC(77-152) [cytosol]UBC(153-228) [cytosol]UBB(77-152) [cytosol]UBC(229-304) [cytosol]UBC(533-608) [cytosol]UBB(153-228) [cytosol]

Reactome Database ID Release 706782592Database 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-6782592.2

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

ChEBI32551PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782633

Reactome Database ID Release 705690781Database 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 705690319Database 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-5690319.29790970Pubmed1998Cleavage of the C-terminus of NEDD8 by UCH-L3Wada, HKito, KCaskey, L SYeh, E TKamitani, TBiochem. Biophys. Res. Commun. 251:688-9212408865Pubmed2002The 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. 16:30-4412210873Pubmed2002ACT and UCH-L1 polymorphisms in Parkinson's disease and age of onsetWang, JianZhao, Chun-YingSi, Yan-MeiLiu, Zhuo-LinChen, BiaoYu, LongMov. Disord. 17:767-712530630Pubmed1989The 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 126:775-889521656Pubmed1998Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolasesLarsen, C NKrantz, B AWilkinson, K DBiochemistry 37:3358-68

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: 6782635

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

UCHL3,SENP8:NEDD8(1-88)

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

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]

UniProtQ96LD8Reactome Database ID Release 706782635Database 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: 29356

Reactome DB_ID: 6782654

EQUAL

Reactome DB_ID: 6782643

UCHL3,SENP8:NEDD8 [cytosol]

UCHL3,SENP8:NEDD8

Reactome DB_ID: 416969

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 5690783

Reactome Database ID Release 706782643Database 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-6782643.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6782635

GO0019784

GO molecular function

Reactome Database ID Release 705690813Database 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 705690808Database 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

Converted 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]

UniProtQ9Y4E8

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: 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 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 70170863Database 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: 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 70170866Database 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-170866.1

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 Latency-associated peptide: Required to maintain the Transforming growth factor beta-1 (TGF-beta-1) chain in a latent state during storage in extracellular matrix (PubMed:28117447). Associates non-covalently with TGF-beta-1 and regulates its activation via interaction with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS, that control activation of TGF-beta-1 (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). Interaction with LRRC33/NRROS regulates activation of TGF-beta-1 in macrophages and microglia (Probable). Interaction with LRRC32/GARP controls activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:22278742, PubMed:19651619). Interaction with integrins (ITGAV:ITGB6 or ITGAV:ITGB8) results in distortion of the Latency-associated peptide chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447).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). Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (PubMed:25893292).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).DOMAIN Latency-associated peptide: The 'straitjacket' and 'arm' domains encircle the Transforming growth factor beta-1 (TGF-beta-1) monomers and are fastened together by strong bonding between Lys-56 and Tyr-103/Tyr-104.DOMAIN Latency-associated peptide: The cell attachment site motif mediates binding to integrins (ITGAV:ITGB6 or ITGAV:ITGB8) (PubMed:28117447). The motif locates to a long loop in the arm domain called the bowtie tail (PubMed:28117447). Integrin-binding stabilizes an alternative conformation of the bowtie tail (PubMed:28117447). Activation by integrin requires force application by the actin cytoskeleton, which is resisted by the 'milieu molecules' (such as LTBP1, LRRC32/GARP and/or LRRC33/NRROS), resulting in distortion of the prodomain and release of the active TGF-beta-1 (PubMed:28117447).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.PTM Latency-associated peptide: N-glycosylated (PubMed:3162913, PubMed:2493139, PubMed:28117447). Deglycosylation leads to activation of Transforming growth factor beta-1 (TGF-beta-1); mechanisms triggering deglycosylation-driven activation of TGF-beta-1 are however unclear (PubMed:2493139).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 70170852Database 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-170852.1Reactome Database ID Release 70170841Database 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-170841.1Reactome Database ID Release 70173476Database 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 702169047Database 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-2169047.1Reactome Database ID Release 702179287Database 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

Converted from EntitySet in Reactome

Reactome DB_ID: 2179332

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 702179328Database 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

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2179287

GO0004843

GO molecular function

Reactome Database ID Release 702179282Database 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 702179291Database 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-2179291.316027725Pubmed2005The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signallingWicks, SJHaros, KMaillard, MSong, LCohen, REDijke, PTChantry, AOncogene 24:8080-422344298Pubmed2012USP15 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 18:429-35

Reactome Database ID Release 705689603Database 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