BioPAX pathway converted from "PTEN Regulation" in the Reactome database. PTEN Regulation PTEN Regulation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Regulation of PTEN gene transcription Regulation of PTEN gene transcription This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> SALL4 recruits NuRD to PTEN gene SALL4 recruits NuRD to PTEN gene This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9919846 1 nucleoplasm GO 0005654 SALL4:PTEN gene [nucleoplasm] SALL4:PTEN gene Reactome DB_ID: 9919844 1 Ghost homologue of PTEN gene [nucleoplasm] Ghost homologue of PTEN gene Reactome http://www.reactome.org Reactome DB_ID: 9884180 1 UniProt:Q8BX22 Sall4 Mus musculus NCBI Taxonomy 10090 UniProt Q8BX22 Chain Coordinates 1 EQUAL 1053 EQUAL Reactome Database ID Release 83 9919846 Database 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=9919846 Reactome R-MMU-8943729 1 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-MMU-8943729.1 Reactome DB_ID: 9824367 1 NuRD complex [nucleoplasm] NuRD complex Converted from EntitySet in Reactome Reactome DB_ID: 9824355 1 MTA1, MTA2, MTA3 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Mta2 [nucleoplasm] Mta1 [nucleoplasm] Mta3 [nucleoplasm] UniProt Q9R190 UniProt Q8K4B0 UniProt Q924K8 Converted from EntitySet in Reactome Reactome DB_ID: 9824365 1 (GATAD2A, GATAD2B) [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 9006136 1 Hdac1:Hdac2 [nucleoplasm] Hdac1:Hdac2 Reactome DB_ID: 573340 1 UniProt:O09106 Hdac1 Hdac1 Hdac1 FUNCTION Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:10615135, PubMed:15542849, PubMed:21960634, PubMed:30279482). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:10615135, PubMed:15542849, PubMed:21960634). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:10615135, PubMed:21960634). Also functions as deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3 and TSHZ3 (By similarity). Deacetylates SP proteins, SP1 and SP3, and regulates their function (By similarity). Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons (By similarity). Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation (By similarity). Deacetylates TSHZ3 and regulates its transcriptional repressor activity (By similarity). Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B (By similarity). Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity (By similarity). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (PubMed:17707228). Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer (PubMed:15226430, PubMed:24736997). Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation (PubMed:15226430). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones (PubMed:30279482).SUBUNIT Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7 (By similarity). The core complex associates with MTA2, MBD2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex (PubMed:11909966, PubMed:9702189). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST and PHF21A/BHC80 (By similarity). The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (By similarity). Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3/SAP45, ARID4B/SAP180, HDAC1 and HDAC2 (By similarity). Found in a trimeric complex with APBB1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3 (By similarity). Interacts with TSHZ3 (via N-terminus); the interaction is direct (By similarity). Component of a RCOR/GFI/KDM1A/HDAC complex (PubMed:17707228). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (By similarity). Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2 (By similarity). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A (PubMed:24413057). Associates with the 9-1-1 complex; interacts with HUS1 (By similarity). Found in a complex with DNMT3A and HDAC7 (PubMed:10984530, PubMed:12616525). Interacts with the non-histone region of MACROH2A1 (PubMed:16107708). Interacts with TRIM28; the interaction recruits HDAC1 to E2F1 and inhibits its acetylation (By similarity). Interacts with SP1; the interaction deacetylates SP1 and regulates its transcriptional activity (By similarity). Interacts with SP3; the interaction deacetylates SP3 and regulates its transcriptional activity (By similarity). In vitro, C(18) ceramides increase this interaction and the subsequent SP3 deacetylation and SP3-mediated repression of the TERT promoter (By similarity). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (By similarity). Interacts with C10orf90/FATS (via its N-terminal); the interaction prevents binding of HDAC1 to CDKN1A/p21 and facilitates the acetylation and stabilization of CDKN1A/p21 (PubMed:20154723). Interacts with CDKN1A/p21 (PubMed:20154723). Interacts with CDK5 complexed to CDK5R1 (p25) (PubMed:20154723). Interacts directly with GFI1 and GFI1B (PubMed:17707228). Interacts with NR1D2 (via C-terminus) (By similarity). Interacts with TSC22D3 isoform 1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity (PubMed:20124407). Interacts with BAZ2A/TIP5, BANP, BCL6, BCOR, BHLHE40/DEC1, BRMS1, BRMS1L, CBFA2T3, CHFR, CIART, CRY1, DAXX, DDIT3/CHOP, DDX5, E4F1, EP300, HCFC1, HDAC9, INSM1, NFE4, NR4A2/NURR1, MIER1, KDM4A, KDM5B, KLF1, MINT, DNMT1, NRIP1, PCAF, PHB2, PRDM6, PRDM16, RB1, RERE, SAMSN1, SAP30L, SETDB1, SMAD3, SMARCAD1, SMARCA4/BRG1, SMYD2, SUV39H1, TGIF, TGIF2, TRAF6, UHRF1, UHRF2, ZMYND15, ZNF431 and ZNF541 (PubMed:14645126, PubMed:11022042, PubMed:12198165, PubMed:12398767, PubMed:11533236, PubMed:15711539, PubMed:16611996, PubMed:11788710, PubMed:10615135, PubMed:16805913, PubMed:24736997, PubMed:19144721, PubMed:18849567, PubMed:24227653, PubMed:20675388, PubMed:20478393, PubMed:22242125, PubMed:15060175, PubMed:16166625, PubMed:16537907, PubMed:16085498, PubMed:15140878, PubMed:15542849, PubMed:15226430, PubMed:21177534). Interacts with KDM5A; this interaction impairs histone deacetylation (PubMed:21960634). Interacts with DNTTIP1 (By similarity). Identified in a histone deacetylase complex that contains DNTTIP1, HDAC1 and MIDEAS; this complex assembles into a tetramer that contains four copies of each protein chain (By similarity). Interacts with CCAR2 (By similarity). Interacts with PPHLN1 (By similarity). Found in a complex with YY1, SIN3A and GON4L (PubMed:21454521). Interacts with CHD4 (By similarity). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (PubMed:28554894). Interacts with SIN3A (PubMed:28554894). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (By similarity). Interacts with ZBTB7A (By similarity). Interacts with SMAD4; positively regulated by ZBTB7A (By similarity). Interacts with PACS2 (By similarity). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC2 (By similarity). Interacts with ZNF638 (By similarity). Interacts with SPHK2. Interacts with ERCC6 (By similarity). Interacts with NSD2 (PubMed:19483677). Interacts with SMYD4 (via MYND-type zinc finger) (By similarity). Interacts with isoform 1 and isoform 3 of PWWP2A in a MTA1-dependent manner (PubMed:30228260). Interacts with PWWP2B (PubMed:30228260, PubMed:34180153). Interacts with ZNF516 and BRCC3; these interactions are enhanced in the presence of PWWP2B (PubMed:34180153). Interacts with SANBR (via the BTB domain) (PubMed:33831416). Interacts with ZNHIT1 (PubMed:19501046).TISSUE SPECIFICITY Widely expressed with higher levels in thymus and testis and lower levels in liver. Present in muscle (at protein level).INDUCTION By interleukin-2.PTM Sumoylated on Lys-444 and Lys-476; which promotes enzymatic activity. Desumoylated by SENP1.PTM Phosphorylation on Ser-421 and Ser-423 promotes enzymatic activity and interactions with NuRD and SIN3 complexes. Phosphorylated by CDK5.PTM Ubiquitinated by CHFR and KCTD11, leading to its degradation by the proteasome.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt O09106 1 EQUAL 482 EQUAL Reactome DB_ID: 573366 1 UniProt:P70288 Hdac2 Hdac2 Hdac2 Yy1bp FUNCTION Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:18754010). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:18754010). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:18754010). Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR (By similarity). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (PubMed:17707228). Also deacetylates non-histone targets: deacetylates TSHZ3, thereby regulating its transcriptional repressor activity (By similarity). May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation (PubMed:15226430). Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A (PubMed:20071335). In addition to protein deacetylase activity, also acts as protein-lysine deacylase by recognizing other acyl groups: catalyzes removal of (2E)-butenoyl (crotonyl) and 2-hydroxyisobutanoyl (2-hydroxyisobutyryl) acyl groups from lysine residues, leading to protein decrotonylation and de-2-hydroxyisobutyrylation, respectively (PubMed:30279482).SUBUNIT Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7 (By similarity). The core complex associates with MTA2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex (By similarity). Component of a RCOR/GFI/KDM1A/HDAC complex (PubMed:17707228). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B, KDM1A, RCOR1 and PHF21A (By similarity). The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (By similarity). Part of a complex containing the core histones H2A, H2B, H3 and H4, DEK and unphosphorylated DAXX (By similarity). Part of a complex containing ATR and CHD4 (By similarity). Forms a heterologous complex at least with YY1 (By similarity). Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1 (By similarity). Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3, ARID4B, HDAC1 and HDAC2 (By similarity). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (By similarity). Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2 (By similarity). Component of a histone deacetylase complex containing DNTTIP1, ZNF541, HDAC1 and HDAC2 (By similarity). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC1 (By similarity). Interacts with SPHK2 (By similarity). Interacts directly with GFI1 and GFI1B (PubMed:17707228). Interacts with SNW1, HDAC7, PRDM6, SAP30, SETDB1 and SUV39H1 (PubMed:11788710, PubMed:12398767, PubMed:10984530, PubMed:9702189, PubMed:16537907). Interacts with the MACROH2A1 (via the non-histone region) (PubMed:16107708). Interacts with ATR, CBFA2T3, DNMT1, SMARCAD1, MINT, HDAC10, HCFC1, NRIP1, KDM4A and PELP1 (PubMed:11533236). Interacts with CHFR and SAP30L (By similarity). Interacts (CK2 phosphorylated form) with SP3 (By similarity). Interacts with TSHZ3 (via its N-terminus) (By similarity). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (By similarity). Interacts with PIMREG (By similarity). Interacts with BCL6 (non-acetylated form) (By similarity). Interacts with CRY1, INSM1 and ZNF431 (PubMed:21177534, PubMed:22391310, PubMed:24227653, PubMed:15226430). Interacts with NACC2 (By similarity). Interacts with MTA1, with a preference for sumoylated MTA1 (By similarity). Interacts with SIX3 (PubMed:17666527). Interacts with BEND3 (By similarity). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (By similarity). Interacts with PWWP2B (PubMed:34180153).PTM S-nitrosylated by GAPDH. In neurons, S-nitrosylation at Cys-262 and Cys-274 does not affect enzyme activity, but induces HDAC2 release from chromatin. This in turn increases acetylation of histones surrounding neurotrophin-dependent gene promoters and promotes their transcription. In embryonic cortical neurons, S-Nitrosylation regulates dendritic growth and branching.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily.CAUTION Was originally thought to be S-nitrosylated and to interact with MTA1 (PubMed:20519513). However, this work was later retracted (PubMed:28314777). Nevertheless, other publications demonstrate that it is S-nitrosylated and there are several publications in the human ortholog demonstrating its interaction with MTA1 (PubMed:18754010, PubMed:20972425). UniProt P70288 1 EQUAL 488 EQUAL Reactome Database ID Release 83 9006136 Database 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=9006136 Reactome R-MMU-9006136 1 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-MMU-9006136.1 Converted from EntitySet in Reactome Reactome DB_ID: 9824345 1 Mi-2 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CHD4 [nucleoplasm] Chd3 [nucleoplasm] UniProt Q6PDQ2 UniProt B1AR17 Reactome DB_ID: 9824337 1 UniProt:Q60973 Rbbp7 Rbbp7 Rbap46 Rbbp7 FUNCTION Core histone-binding subunit that may target chromatin remodeling factors, histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the type B histone acetyltransferase (HAT) complex, which is required for chromatin assembly following DNA replication; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; and the PRC2/EED-EZH2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex (By similarity).SUBUNIT Binds directly to helix 1 of the histone fold of histone H4, a region that is not accessible when H4 is in chromatin. Subunit of the type B histone acetyltransferase (HAT) complex, composed of RBBP7 and HAT1. Subunit of the core histone deacetylase (HDAC) complex, which is composed of HDAC1, HDAC2, RBBP4 and RBBP7. The core HDAC complex associates with SIN3A, ARID4B/SAP180, SAP18, SAP30, SAP130, SUDS3/SAP45 and possibly ARID4A/RBP1 and ING1 to form the SIN3 HDAC complex. The core HDAC complex may also associate with MTA2, MBD3, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylase complex (the NuRD complex). The NuRD complex may also interact with MBD3L1 and MBD3L2. Interacts with MTA1. Subunit of the PRC2/EED-EZH2 complex, which is composed of at least EED, EZH2, RBBP4, RBBP7 and SUZ12. The PRC2/EED-EZH2 complex may also associate with HDAC1. Component of the NURF-1 ISWI chromatin remodeling complex (also called the nucleosome-remodeling factor (NURF) complex) at least composed of SMARCA1; BPTF; RBBP4 and RBBP7 (By similarity). Within the complex interacts with SMARCA1 (By similarity). Interacts with the viral protein-binding domain of the retinoblastoma protein (RB1). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP. Interacts with CENPA (By similarity). Interacts with BRCA1 (By similarity). Interacts with HDAC7 (PubMed:10984530). Interacts with SUV39H1 (PubMed:11788710). Interacts with PWWP2B (PubMed:34180153).TISSUE SPECIFICITY Higher levels in brain, thymus, lung, spleen, kidney, testis, and ovary/uterus; lower levels in heart, liver, and muscle.SIMILARITY Belongs to the WD repeat RBAP46/RBAP48/MSI1 family. UniProt Q60973 2 EQUAL 425 EQUAL Reactome DB_ID: 9824348 1 UniProt:Q9Z2D8 Mbd3 Mbd3 Mbd3 FUNCTION Acts as transcriptional repressor and plays a role in gene silencing. Does not bind DNA by itself. Binds to DNA with a preference for sites containing methylated CpG dinucleotides (in vitro). Binds to a lesser degree DNA containing unmethylated CpG dinucleotides (By similarity). Recruits histone deacetylases and DNA methyltransferases.SUBUNIT Heterodimer with MBD2. Part of the NuRD and the MeCP1 complex. Interacts with BCL6, HDAC1, MTA2, DNMT1, p66-alpha and p66-beta (By similarity). Does not interact with PWWP2A and PWWP2B (PubMed:30228260, PubMed:30327463).TISSUE SPECIFICITY Highly expressed in brain, heart, kidney, liver, lung, skeletal muscle, spleen and testis. Detected at lower levels in embryonic stem cells. UniProt Q9Z2D8 1 EQUAL 291 EQUAL Reactome DB_ID: 573325 1 UniProt:Q60972 Rbbp4 Rbbp4 Rbap48 Rbbp4 FUNCTION Core histone-binding subunit that may target chromatin assembly factors, chromatin remodeling factors and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the chromatin assembly factor 1 (CAF-1) complex, which is required for chromatin assembly following DNA replication and DNA repair; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; the PRC2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex.SUBUNIT Binds directly to helix 1 of the histone fold of histone H4, a region that is not accessible when H4 is in chromatin. Subunit of the chromatin assembly factor 1 (CAF-1) complex, which is composed of RBBP4, CHAF1B and CHAF1A (By similarity). Subunit of the core histone deacetylase (HDAC) complex, which is composed of HDAC1, HDAC2, RBBP4 and RBBP7 (By similarity). The core HDAC complex associates with SIN3A, ARID4B/SAP180, SAP18, SAP30, SAP130, SUDS3/SAP45 and possibly ARID4A/RBP1 and ING1 to form the SIN3 HDAC complex (Probable). The core HDAC complex may also associate with MTA2, MBD3, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylase complex (the NuRD complex) (By similarity). The NuRD complex may also interact with MBD3L1 and MBD3L2 (By similarity). Interacts with MTA1 (By similarity). Component of the PRC2 complex, which consists of the core subunits EED, EZH1 or EZH2, SUZ12, and RBBP4, and various combinations of accessory subunits including AEBP2, JARID2, PHF19, MTF2 and EPOP (PubMed:19026780). Forms a monomeric PRC2.2 (class 2) complex consisting of at least SUZ12, RBBP4, AEBP2 and JARID2 (By similarity). Forms a dimeric PRC2.1 (class 1, PRC-PCL) complex consisting of at least SUZ12, RBBP4, and PHF19; PHF19 stabilizes the dimeric structure which enhances PRC2 interaction with chromatin (By similarity). Component of the NURF-1 ISWI chromatin remodeling complex (also called the nucleosome-remodeling factor (NURF) complex) at least composed of SMARCA1; BPTF; RBBP4 and RBBP7 (PubMed:10866654). Within the complex interacts with SMARCA1 (By similarity). Interacts with the ISWI chromatin remodeling complex component SMARCA5; the interaction is direct (By similarity). Interacts with SUV39H1 and HDAC7 (PubMed:10984530, PubMed:11788710). Interacts with the viral protein-binding domain of the retinoblastoma protein (RB1) (By similarity). Interacts with SPEN/MINT (By similarity). Interacts with BRCA1 (By similarity). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP (By similarity). Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2 (By similarity). The complex exists in quiescent cells where it represses cell cycle-dependent genes (By similarity). It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2 (By similarity). Interacts with PHF6 (By similarity). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (PubMed:28554894). Interacts with ERCC6 (By similarity). Interacts with ZNF827; the interaction is direct and recruits RBBP4 to telomeres (By similarity). Interacts with ARMC12 (via ARM domains) (By similarity). Interacts with PWWP2B (PubMed:34180153).TISSUE SPECIFICITY Higher levels in brain, thymus, lung, spleen, kidney, testis, and ovary/uterus; lower levels in heart, liver, and muscle.SIMILARITY Belongs to the WD repeat RBAP46/RBAP48/MSI1 family. UniProt Q60972 2 EQUAL 425 EQUAL Reactome Database ID Release 83 9824367 Database 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=9824367 Reactome R-MMU-4657018 1 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-MMU-4657018.1 Reactome DB_ID: 9919850 1 SALL4:NuRD:PTEN gene [nucleoplasm] SALL4:NuRD:PTEN gene Reactome DB_ID: 9919844 1 Reactome DB_ID: 9919848 1 SALL4:NuRD [nucleoplasm] SALL4:NuRD Reactome DB_ID: 9884180 1 1 EQUAL 1053 EQUAL Reactome DB_ID: 9824367 1 Reactome Database ID Release 83 9919848 Database 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=9919848 Reactome R-MMU-8943778 1 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-MMU-8943778.1 Reactome Database ID Release 83 9919850 Database 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=9919850 Reactome R-MMU-8943781 1 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-MMU-8943781.1 Reactome Database ID Release 83 9919852 Database 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=9919852 Reactome R-MMU-8943780 1 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-MMU-8943780.1 SALL4 recruits the transcriptional repressor complex NuRD, containing histone deacetylases HDAC1 and HDAC2, to the PTEN gene promoter (Lu et al 2009, Gao et al. 2013). SALL4 may also recruit DNA methyltransferases (DNMTs) to the PTEN promoter (Yang et al. 2012). 23287862 Pubmed 2013 Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex Gao, Chong Dimitrov, Todor Yong, Kol Jia Tatetsu, Hiro Jeong, Ha-Won Luo, Hongbo R Bradner, James E Tenen, Daniel G Chai, Li Blood 121:1413-21 19440552 Pubmed 2009 Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex Lu, J Jeong, HW Kong, N Yang, Y Carroll, J Luo, HR Silberstein, LE Yupoma, LE Chai, L PLoS One 4:e5577 22128185 Pubmed 2012 Stem cell gene SALL4 suppresses transcription through recruitment of DNA methyltransferases Yang, Jianchang Corsello, Tyler R Ma, Yupo J. Biol. Chem. 287:1996-2005 inferred by electronic annotation IEA GO IEA MECOM (EVI1) recruits polycomb repressor complexes (PRCs) to the PTEN gene promoter MECOM (EVI1) recruits polycomb repressor complexes (PRCs) to the PTEN gene promoter This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9919858 1 MECOM:PTEN gene [nucleoplasm] MECOM:PTEN gene Reactome DB_ID: 9919844 1 Reactome DB_ID: 9919854 1 UniProt:P14404 Mecom UniProt P14404 1 EQUAL 1051 EQUAL Reactome Database ID Release 83 9919858 Database 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=9919858 Reactome R-MMU-8943810 1 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-MMU-8943810.1 Converted from EntitySet in Reactome Reactome DB_ID: 9919856 1 PRC1.4,PRC2 (EZH2) core [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 9919862 1 MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene Reactome DB_ID: 9919860 1 MECOM:(PRC1.4,PRC2 (EZH2) core) [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core) Converted from EntitySet in Reactome Reactome DB_ID: 9919856 1 Reactome DB_ID: 9919854 1 1 EQUAL 1051 EQUAL Reactome Database ID Release 83 9919860 Database 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=9919860 Reactome R-MMU-8943820 1 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-MMU-8943820.1 Reactome DB_ID: 9919844 1 Reactome Database ID Release 83 9919862 Database 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=9919862 Reactome R-MMU-8943821 1 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-MMU-8943821.1 Reactome Database ID Release 83 9919864 Database 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=9919864 Reactome R-MMU-8943817 1 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-MMU-8943817.1 The transcription factor MECOM (EVI1) can associate with the polycomb repressor complexes (PRCs) and recruit them to the promoter of the PTEN gene (Song et al. 2009). Both the BMI1-containing PRC, supposedly PRC1.4, and the EZH2-containing PRC2 complex are recruited to the PTEN promoter, resulting in transcriptional silencing of the PTEN gene (Song et al. 2009, Yoshimi et al. 2011). Since the exact composition of the EZH2-containing PRC2 at the PTEN promoter is not known, the core EZH2-PRC2 complex is shown. 19884659 Pubmed 2009 The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells Song, Li-Bing Li, J Liao, Wen-Ting Feng, Yan Yu, Chun-Ping Hu, Li-Juan Kong, Qing-Li Xu, Li-Hua Zhang, Xing Liu, Wan-Li Li, Man-Zhi Zhang, L Kang, Tie-Bang Fu, Li-Wu Huang, Wen-Lin Xia, Yun-Fei Tsao, Sai Wah Li, Mengfeng Band, Vimla Band, Hamid Shi, Qing-Hua Zeng, Yi-Xin Zeng, Mu-Sheng J. Clin. Invest. 119:3626-36 21289308 Pubmed 2011 Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins Yoshimi, Akihide Goyama, Susumu Watanabe-Okochi, Naoko Yoshiki, Yumiko Nannya, Yasuhito Nitta, Eriko Arai, Shunya Sato, Tomohiko Shimabe, Munetake Nakagawa, Masahiro Imai, Yoichi Kitamura, Toshio Kurokawa, Mineo Blood 117:3617-28 inferred by electronic annotation IEA GO IEA 2.7.11.1 mTORC1 phosphorylates MAF1 mTORC1 phosphorylates MAF1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9919967 1 cytosol GO 0005829 UniProt:Q9D0U6 Maf1 UniProt Q9D0U6 1 EQUAL 256 EQUAL Reactome DB_ID: 113592 3 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 29370 3 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 9919972 1 O-phospho-L-serine at 60 (in Homo sapiens) 60 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 68 (in Homo sapiens) 68 EQUAL O-phospho-L-serine at 75 (in Homo sapiens) 75 EQUAL 1 EQUAL 256 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9831936 lysosomal membrane GO 0005765 Active mTORC1 complex [lysosomal membrane] Active mTORC1 complex Reactome DB_ID: 9831856 1 RHEB:GTP [lysosomal membrane] RHEB:GTP Reactome DB_ID: 9831852 1 UniProt:Q921J2 UniProt Q921J2 1 EQUAL 181 EQUAL Reactome DB_ID: 29438 1 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI 37565 Reactome Database ID Release 83 9831856 Database 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=9831856 Reactome R-MMU-165189 1 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-MMU-165189.1 Reactome DB_ID: 9831934 1 mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 [lysosomal membrane] mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Reactome DB_ID: 9831872 1 mTORC1 [cytosol] mTORC1 Reactome DB_ID: 9831862 1 UniProt:Q9DCJ1 Mlst8 UniProt Q9DCJ1 1 EQUAL 326 EQUAL Reactome DB_ID: 9831870 1 UniProt:Q8K4Q0 Rptor UniProt Q8K4Q0 1 EQUAL 1335 EQUAL Reactome DB_ID: 9831866 1 UniProt:Q9JLN9 Mtor UniProt Q9JLN9 1 EQUAL 2549 EQUAL Reactome Database ID Release 83 9831872 Database 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=9831872 Reactome R-MMU-377400 1 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-MMU-377400.1 Reactome DB_ID: 9831932 1 Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 [lysosomal membrane] Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Reactome DB_ID: 9831876 1 UniProt:Q8BGD6 Slc38a9 UniProt Q8BGD6 1 EQUAL 561 EQUAL Reactome DB_ID: 9831930 1 Ragulator:RagA,B:GTP:RagC,D:GDP [lysosomal membrane] Ragulator:RagA,B:GTP:RagC,D:GDP Reactome DB_ID: 9831898 1 Ragulator [lysosomal membrane] Ragulator Reactome DB_ID: 9831892 1 UniProt:Q8CF66 Lamtor4 UniProt Q8CF66 1 EQUAL 99 EQUAL Reactome DB_ID: 9831884 1 UniProt:Q9JHS3 Lamtor2 UniProt Q9JHS3 1 EQUAL 125 EQUAL Reactome DB_ID: 9831888 1 UniProt:O88653 Lamtor3 UniProt O88653 1 EQUAL 124 EQUAL Reactome DB_ID: 9831896 1 UniProt:Q9D1L9 Lamtor5 UniProt Q9D1L9 1 EQUAL 91 EQUAL Reactome DB_ID: 9831880 1 UniProt:Q9CQ22 Lamtor1 UniProt Q9CQ22 2 EQUAL 161 EQUAL Reactome Database ID Release 83 9831898 Database 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=9831898 Reactome R-MMU-5653921 1 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-MMU-5653921.1 Reactome DB_ID: 9831928 1 RagA,B:GTP:RagC,D:GDP [cytosol] RagA,B:GTP:RagC,D:GDP Converted from EntitySet in Reactome Reactome DB_ID: 9831926 1 RRAGC,RRAGD:GDP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 9831912 1 RRAGA, RRAGB:GTP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 83 9831928 Database 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=9831928 Reactome R-MMU-5653945 1 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-MMU-5653945.1 Reactome Database ID Release 83 9831930 Database 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=9831930 Reactome R-MMU-5653979 1 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-MMU-5653979.1 Reactome Database ID Release 83 9831932 Database 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=9831932 Reactome R-MMU-8952725 1 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-MMU-8952725.1 Reactome Database ID Release 83 9831934 Database 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=9831934 Reactome R-MMU-5653972 1 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-MMU-5653972.1 Reactome Database ID Release 83 9831936 Database 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=9831936 Reactome R-MMU-165678 1 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-MMU-165678.1 GO 0004674 GO molecular function Reactome Database ID Release 83 9919973 Database 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=9919973 Reactome Database ID Release 83 9919975 Database 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=9919975 Reactome R-MMU-8944454 1 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-MMU-8944454.1 Activated mTORC1 complex phosphorylates the transcription factor MAF1 on serine residues S60, S68 and S75 (Shor et al. 2010, Michels et al. 2010). mTORC1-mediated phosphorylation of MAF1 inhibits translocation of MAF1 to the nucleus (Shor et al. 2010). 20233713 Pubmed 2010 Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells Shor, Boris Wu, Jiang Shakey, Quazi Toral-Barza, Lourdes Shi, Celine Follettie, Max Yu, Ker J. Biol. Chem. 285:15380-92 20516213 Pubmed 2010 mTORC1 directly phosphorylates and regulates human MAF1 Michels, Annemieke A Robitaille, Aaron M Buczynski-Ruchonnet, Diane Hodroj, Wassim Reina, Jaime H Hall, Michael N Hernandez, Nouria Mol. Cell. Biol. 30:3749-57 inferred by electronic annotation IEA GO IEA MAF1 translocates to the nucleus MAF1 translocates to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9919967 1 1 EQUAL 256 EQUAL Reactome DB_ID: 9919965 1 1 EQUAL 256 EQUAL Reactome Database ID Release 83 9919977 Database 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=9919977 Reactome R-MMU-8944457 1 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-MMU-8944457.1 Phosphorylation of MAF1 by the activated mTORC1 complex inhibits translocation of MAF1 to the nucleus, and hence its transcriptional activity, but the mechanism has not been elucidated (Shor et al. 2010). inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 83 9919978 Database 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=9919978 Reactome DB_ID: 9831936 Reactome Database ID Release 83 9933784 Database 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=9933784 Reactome R-MMU-8943724 1 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-MMU-8943724.1 Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016). 18172008 Pubmed 2008 Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis Escrivà, Maria Peiró, Sandra Herranz, Nicolás Villagrasa, Patricia Dave, Natàlia Montserrat-Sentís, Bàrbara Murray, Stephen A Francí, Clara Gridley, T Virtanen, Ismo García de Herreros, Antonio Mol. Cell. Biol. 28:1528-40 26910647 Pubmed 2016 MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription Li, Yue Tsang, Chi Kwan Wang, Suihai Li, Xiao-Xing Yang, Yang Fu, Liwu Huang, Wenlin Li, Ming Wang, Hui-Yun Zheng, X F Steven Hepatology 63:1928-42 11781575 Pubmed 2001 The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling Virolle, T Adamson, Eileen D Baron, V Birle, D Mercola, D Mustelin, T de Belle, I Nat. Cell Biol. 3:1124-8 25728608 Pubmed 2015 SLUG is a direct transcriptional repressor of PTEN tumor suppressor Uygur, Berna Abramo, Katrina Leikina, Evgenia Vary, Calvin Liaw, Lucy Wu, Wen-Shu Prostate 75:907-16 17974977 Pubmed 2007 Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras Vasudevan, Krishna Murthi Burikhanov, Ravshan Goswami, Anindya Rangnekar, Vivek M Cancer Res. 67:10343-50 18487508 Pubmed 2008 SALL4 is a key regulator of survival and apoptosis in human leukemic cells Yang, Jianchang Chai, Li Gao, Chong Fowles, Taylor C Alipio, Zaida Dang, Hien Xu, Dan Fink, Louis M Ward, David C Ma, Yupo Blood 112:805-13 16702404 Pubmed 2006 Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1 Zhang, Chun-Li Zou, Yuhua Yu, Ruth T Gage, Fred H Evans, Ronald M Genes Dev. 20:1308-20 16418168 Pubmed 2006 Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells Shen, Ying H Zhang, Lin Gan, Yehua Wang, Xinwen Wang, Jian LeMaire, Scott A Coselli, Joseph S Wang, Xing Li J. Biol. Chem. 281:7727-36 11378386 Pubmed 2001 Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN Patel, L Pass, I Coxon, P Downes, C P Smith, S A MacPhee, C H Curr. Biol. 11:764-8 11545734 Pubmed 2001 Regulation of PTEN transcription by p53 Stambolic, V MacPherson, D Sas, D Lin, Y Snow, B Jang, Y Benchimol, S Mak, T W Mol. Cell 8:317-25 inferred by electronic annotation IEA GO IEA Regulation of PTEN localization Regulation of PTEN localization This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PTEN undergoes monoubiquitination PTEN undergoes monoubiquitination This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9821134 1 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ubiquitin (Ubc 4) [cytosol] Ubiquitin (Ubb 1) [cytosol] Ubiquitin (Ubc 6) [cytosol] Ubiquitin (Ubc 2) [cytosol] Ubiquitin (Ubc 3) [cytosol] Ubiquitin (Ubc 7) [cytosol] Rps27a [cytosol] Ubiquitin (Ubc 5) [cytosol] Ubiquitin (Ubc 1) [cytosol] Ubiquitin (Ubc 8) [cytosol] Ubiquitin (Pps27a) [cytosol] Ubiquitin related 1 (Ubc r1) [cytosol] Ubiquitin (Uba52) [cytosol] UniProt P0CG50 UniProt P0CG49 UniProt P62983 UniProt P62984 Reactome DB_ID: 9839214 1 UniProt:O08586 Pten UniProt O08586 2 EQUAL 403 EQUAL Reactome DB_ID: 9909383 1 ubiquitinylated lysine (Ub [cytosol]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine [MOD:01148] ubiquitinylated lysine (Ub [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9909391 XIAP,NEDD4 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0061630 GO molecular function Reactome Database ID Release 83 9909392 Database 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=9909392 Reactome Database ID Release 83 9909394 Database 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=9909394 Reactome R-MMU-6807106 1 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-MMU-6807106.1 When present at low levels in the cell, the E3 ubiquitin ligase XIAP monoubiquitinates PTEN (Van Themsche et al. 2009). NEDD4 (NEDD4-1) can also monoubiquitinate PTEN (Trotman et al. 2007). Monoubiquitination of PTEN on at least lysine residues K13 and K289 causes translocation of PTEN from the cytosol to the nucleus (Trotman et al. 2007, Van Themsche et al. 2009). 19473982 Pubmed 2009 X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization Van Themsche, Céline Leblanc, Valérie Parent, Sophie Asselin, Eric J. Biol. Chem. 284:20462-6 17218261 Pubmed 2007 Ubiquitination regulates PTEN nuclear import and tumor suppression Trotman, Lloyd C Wang, Xinjiang Alimonti, Andrea Chen, Zhenbang Teruya-Feldstein, Julie Yang, Haijuan Pavletich, Nikola P Carver, Brett S Cordon-Cardo, Carlos Erdjument-Bromage, H Tempst, P Chi, Sung-Gil Kim, Hyo-Jong Misteli, Tom Jiang, Xuejun Pandolfi, Pier Paolo Cell 128:141-56 inferred by electronic annotation IEA GO IEA Monoubiquitinated PTEN translocates to the nucleus Monoubiquitinated PTEN translocates to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9909383 1 ubiquitinylated lysine (Ub [cytosol]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine (Ub [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 9909387 1 ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9909389 Database 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=9909389 Reactome R-MMU-6807105 1 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-MMU-6807105.1 Monoubiquitinated PTEN translocates to the nucleus. Lysine residues K13 and K289 of PTEN are important monoubiquitination targets and their mutation abrogates PTEN nuclear localization (Trotman et al. 2007). inferred by electronic annotation IEA GO IEA 3.4.19.12 USP7 deubiquitinates monoubiquitinated PTEN USP7 deubiquitinates monoubiquitinated PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9909387 1 ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 113518 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 9899592 1 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9820725 2 Ub [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ubiquitin (Pps27a) [nucleoplasm] Ubiquitin (Ubc 6) [nucleoplasm] Ubiquitin (Uba52) [nucleoplasm] Ubiquitin (Ubc 3) [nucleoplasm] Ubiquitin (Ubc 5) [nucleoplasm] Ubiquitin (Ubc 7) [nucleoplasm] Ubiquitin related 1 (Ubc r1) [nucleoplasm] Ubiquitin (Ubc 8) [nucleoplasm] Ubiquitin (Ubb 1) [nucleoplasm] Ubiquitin (Ubc 2) [nucleoplasm] Ubiquitin (Ubc 4) [nucleoplasm] Ubiquitin (Ubc 1) [nucleoplasm] Rps27a [nucleoplasm] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9885022 UniProt:Q6A4J8 Usp7 UniProt Q6A4J8 1 EQUAL 1102 EQUAL GO 0004843 GO molecular function Reactome Database ID Release 83 9885051 Database 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=9885051 Reactome Database ID Release 83 9909396 Database 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=9909396 Reactome R-MMU-6807118 1 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-MMU-6807118.1 USP7 (HAUSP) deubiquitinates monoubiquitinated nuclear PTEN, thus promoting relocalization of PTEN to the cytosol. USP7-mediated deubiquitination of PTEN is negatively regulated by PML in the presence of DAXX, but the exact mechanism has not been elucidated (Song et al. 2008). 18716620 Pubmed 2008 The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network Song, MS Salmena, Leonardo Carracedo, Arkaitz Egia, Ainara Lo-Coco, F Teruya-Feldstein, Julie Pandolfi, Pier Paolo Nature 455:813-7 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 83 9909397 Database 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=9909397 Reactome DB_ID: 9884584 UniProt:Q60953 UniProt Q60953 1 EQUAL 882 EQUAL Deubiquitinated PTEN translocates to the cytosol Deubiquitinated PTEN translocates to the cytosol This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9899592 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9839214 1 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9909399 Database 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=9909399 Reactome R-MMU-6807126 1 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-MMU-6807126.1 After nuclear monoubiquitinated PTEN gets deubiquitinated by USP7 (HAUSP), it translocates to the cytosol (Song et al. 2008). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 83 9933608 Database 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=9933608 Reactome R-MMU-8948747 1 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-MMU-8948747.1 When monoubiquitinated by E3 ubiquitin ligases XIAP and NEDD4, PTEN translocates from the cytosol to the nucleus (Trotman et al. 2007, Van Themsche et al. 2009). USP7 (HAUSP)-mediated deubiquitination of monoubiquitinated nuclear PTEN promotes relocalization of PTEN to the cytosol (Song et al. 2008). inferred by electronic annotation IEA GO IEA Regulation of PTEN stability and activity Regulation of PTEN stability and activity This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NEDD4, WWP2, CHIP and XIAP polyubiquitinate PTEN NEDD4, WWP2, CHIP and XIAP polyubiquitinate PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9821134 3 Reactome DB_ID: 9839214 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9909402 1 ubiquitinylated lysine (polyubiquitin chain [cytosol]) at unknown position 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9909408 NEDD4,STUB1,WWP2 and XIAP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity XIAP [cytosol] Stub1 [cytosol] Nedd4 [cytosol] Wwp2 [cytosol] UniProt Q60989 UniProt Q9WUD1 UniProt P46935 UniProt Q9DBH0 Reactome Database ID Release 83 9909409 Database 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=9909409 Reactome Database ID Release 83 9909411 Database 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=9909411 Reactome R-MMU-6807134 1 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-MMU-6807134.1 Several ubiquitin ligases, including NEDD4 (Wang et al. 2007), STUB1 (CHIP) (Ahmed et al. 2012), WWP2 (Maddika et al. 2011) and XIAP (Van Themsche et al. 2009) can polyubiquitinate PTEN, targeting it for degradation. 17218260 Pubmed 2007 NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN Wang, Xinjiang Trotman, Lloyd C Koppie, Theresa Alimonti, Andrea Chen, Zhenbang Gao, Zhonghua Wang, Junru Erdjument-Bromage, H Tempst, P Cordon-Cardo, Carlos Pandolfi, Pier Paolo Jiang, Xuejun Cell 128:129-39 21532586 Pubmed 2011 WWP2 is an E3 ubiquitin ligase for PTEN Maddika, Subbareddy Kavela, Sridhar Rani, Neelam Palicharla, Vivek Reddy Pokorny, Jenny L Sarkaria, Jann N Chen, J Nat. Cell Biol. 13:728-33 22427670 Pubmed 2012 The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation Ahmed, Syed Feroj Deb, Satamita Paul, Indranil Chatterjee, Anirban Mandal, Tapashi Chatterjee, Uttara Ghosh, Mrinal K J. Biol. Chem. 287:15996-6006 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT phosphorylates MKRN1 AKT phosphorylates MKRN1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9862899 1 UniProt:Q9QXP6 Mkrn1 UniProt Q9QXP6 1 EQUAL 482 EQUAL Reactome DB_ID: 113592 1 Reactome DB_ID: 9920165 1 O-phospho-L-serine at 109 (in Homo sapiens) 109 EQUAL 1 EQUAL 482 EQUAL Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9838182 p-T,p-S-AKT [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-T308,S473-AKT1 [cytosol] UniProt P31750 Reactome Database ID Release 83 9838183 Database 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=9838183 Reactome Database ID Release 83 9920167 Database 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=9920167 Reactome R-MMU-8948757 1 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-MMU-8948757.1 GO 0043491 GO biological process AKT1 (and possibly AKT2 and AKT3), activated in response to EGF treatment, phosphorylates MKRN1, an E3 ubiquitin ligase, on serine residue S109. AKT-mediated phosphorylation results in stabilization of MKRN1, protecting it from ubiquitination and proteasome-mediated degradation (Lee et al. 2015). 26183061 Pubmed 2015 PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis Lee, Min-Sik Jeong, Man-Hyung Lee, Hyun-Woo Han, Hyun-Ji Ko, Aram Hewitt, SM Kim, Jae-Hoon Chun, Kyung-Hee Chung, Joon-Yong Lee, Cheolju Cho, Hanbyoul Song, Jaewhan Nat Commun 6:7769 inferred by electronic annotation IEA GO IEA MKRN1 polyubiquitinates PTEN MKRN1 polyubiquitinates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9821134 3 Reactome DB_ID: 9839214 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9909414 1 ubiquitinylated lysine (K48polyUb [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9920165 O-phospho-L-serine at 109 (in Homo sapiens) 109 EQUAL 1 EQUAL 482 EQUAL Reactome Database ID Release 83 9920168 Database 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=9920168 Reactome Database ID Release 83 9920170 Database 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=9920170 Reactome R-MMU-8948775 1 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-MMU-8948775.1 The C-terminal region of the E3 ubiquitin ligase MKRN1 interacts with PTEN and polyubiquitinates it on lysine residue K289, via K48 linkage. AKT-mediated phosphorylation of MKRN1 on serine residue S109 is a pre-requisite for MKRN1 stabilization and MKRN1-mediated ubiquitination of PTEN. MKRN1 is implicated as an oncogene in cervical cancer (Lee et al. 2015). inferred by electronic annotation IEA GO IEA 2.4.2.30 TNKS and TNKS2 PARylate PTEN TNKS and TNKS2 PARylate PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29360 3 NAD(1-) [ChEBI:57540] NAD(1-) NAD(+) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD anion ChEBI 57540 Reactome DB_ID: 9839214 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9920172 1 adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 40 (in Homo sapiens) 40 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 150 (in Homo sapiens) 150 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 326 (in Homo sapiens) 326 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 197277 3 nicotinamide [ChEBI:17154] nicotinamide ChEBI 17154 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9886656 TNKS1/2 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TNKS2 [cytosol] TNKS [cytosol] UniProt Q3UES3 UniProt Q6PFX9 GO 0003950 GO molecular function Reactome Database ID Release 83 9920173 Database 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=9920173 Reactome Database ID Release 83 9920175 Database 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=9920175 Reactome R-MMU-8948800 1 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-MMU-8948800.1 PTEN can bind tankyrases TNKS (TNKS1) and TNKS2. The interaction involves the tankyrase binding motif at the N-terminus of PTEN (RYQEDG). TNKS and TNKS2 poly-ADP-ribosylate (PARylate) PTEN on glutamic acid residues E40 and E150 and on aspartic acid residue D326. PTEN PARylation is a pre-requisite for RNF146-mediated ubiquitination of PTEN (Li et al. 2015). 25547115 Pubmed 2015 Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth Li, N Zhang, Yajie Han, Xin Liang, Ke Wang, Jiadong Feng, Lin Wang, W Songyang, Z Lin, Chunru Yang, Liuqing Yu, Yonghao Chen, J Genes Dev. 29:157-70 inferred by electronic annotation IEA GO IEA RNF146 polyubiquitinates PARylated PTEN RNF146 polyubiquitinates PARylated PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9821134 9 Reactome DB_ID: 9920172 1 adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 40 (in Homo sapiens) 40 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 150 (in Homo sapiens) 150 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 326 (in Homo sapiens) 326 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 9913186 1 adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 40 (in Homo sapiens) 40 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 150 (in Homo sapiens) 150 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 326 (in Homo sapiens) 326 EQUAL ubiquitinylated lysine (polyubiquitin chain [cytosol]) at 342 (in Homo sapiens) 342 EQUAL ubiquitinylated lysine (polyubiquitin chain [cytosol]) at 344 (in Homo sapiens) 344 EQUAL ubiquitinylated lysine (polyubiquitin chain [cytosol]) at 349 (in Homo sapiens) 349 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9886636 UniProt:Q9CZW6 UniProt Q9CZW6 1 EQUAL 359 EQUAL Reactome Database ID Release 83 9920176 Database 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=9920176 Reactome Database ID Release 83 9920178 Database 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=9920178 Reactome R-MMU-8948832 1 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-MMU-8948832.1 The E3 ubiquitin ligase RNF146 possesses a PAR recognition domain (WWE) which binds to PARylated PTEN. RNF146 polyubiquitinates PARylated PTEN, with lysine residues K342, K344 and K349 as major ubiquitination sites. RNF146-mediated ubiquitination targets PTEN for proteasome-mediated degradation (Li et al. 2015). inferred by electronic annotation IEA GO IEA Proteasome degrades polyubiquitinated PTEN Proteasome degrades polyubiquitinated PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9913188 1 PolyUb-PTEN, K48polyUb-K289-PTEN, PolyUb-K324,K344,K349-RibC-E40,E150,D326-PTEN [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Pten [cytosol] Pten [cytosol] Converted from EntitySet in Reactome Reactome DB_ID: 9821134 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9821204 26S proteasome [cytosol] 26S proteasome Reactome DB_ID: 9821202 1 Ghost homologue of SEM1 [cytosol] Ghost homologue of SEM1 Reactome DB_ID: 9821142 1 UniProt:O55234 Psmb5 Psmb5 Psmb5 FUNCTION 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 (PubMed:16857966, PubMed:22341445). Directly interacts with POMP (By similarity). Interacts with ABCB1 and TAP1 (By similarity).TISSUE SPECIFICITY Expressed in uterus at the embryo implantation site.INDUCTION Up-regulated in embryonic fibroblasts and neuroblastoma cells by antioxidants through the Nrf2-ARE pathway (at protein level). Up-regulated by the antioxidant dithiolethione (D3T) in liver, small intestine and brain (at protein level). Down-regulated under lithium treatment.SIMILARITY Belongs to the peptidase T1B family. UniProt O55234 60 EQUAL 263 EQUAL Reactome DB_ID: 9821182 1 UniProt:Q9CR00 Psmd9 UniProt Q9CR00 1 EQUAL 223 EQUAL Reactome DB_ID: 1236823 1 UniProt:Q9QUM9 Psma6 Psma6 Psma6 FUNCTION 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 (PubMed:16857966, PubMed:22341445). Interacts with ALKBH4 (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor tissues (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt Q9QUM9 1 EQUAL 246 EQUAL Reactome DB_ID: 1236795 1 UniProt:Q9R1P1 Psmb3 Psmb3 Psmb3 FUNCTION Non-catalytic 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.TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt Q9R1P1 2 EQUAL 205 EQUAL Reactome DB_ID: 1236775 1 UniProt:P70195 Psmb7 Psmb7 Psmb7 Mmc14 FUNCTION 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.INDUCTION Up-regulated by the antioxidant dithiolethione (D3T) in colon (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt P70195 44 EQUAL 277 EQUAL Reactome DB_ID: 9821148 1 UniProt:P46471 UniProt P46471 2 EQUAL 433 EQUAL Reactome DB_ID: 9821156 1 UniProt:P62334 UniProt P62334 1 EQUAL 389 EQUAL Reactome DB_ID: 1236756 1 UniProt:Q9R1P3 Psmb2 Psmb2 Psmb2 FUNCTION Non-catalytic 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.TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt Q9R1P3 1 EQUAL 201 EQUAL Reactome DB_ID: 9821136 1 UniProt:O35593 UniProt O35593 1 EQUAL 310 EQUAL Reactome DB_ID: 1236802 1 UniProt:Q9R1P4 Psma1 Psma1 Psma1 FUNCTION 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 (PubMed:16857966). Interacts with NOTCH3 (By similarity). Interacts with ZFAND1 (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor tissues. Up-regulated by the antioxidant dithiolethione (D3T) in liver, lung and colon (at the protein level).PTM C-terminal extension is partially cleaved off by limited proteolysis leading to a conversion of the proteasome from its latent into its active form.SIMILARITY Belongs to the peptidase T1A family. UniProt Q9R1P4 1 EQUAL 263 EQUAL Reactome DB_ID: 9821146 1 UniProt:P62192 UniProt P62192 2 EQUAL 440 EQUAL Reactome DB_ID: 9821174 1 UniProt:Q8BJY1 Psmd5 UniProt Q8BJY1 2 EQUAL 504 EQUAL Reactome DB_ID: 1236868 1 UniProt:O70435 Psma3 Psma3 Psma3 FUNCTION 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 (PubMed:16857966, PubMed:22341445). Interacts with AURKB. Interacts with CDKN1A. Interacts with MDM2 and RB1. Interacts with the C-terminus of TBXA2R isoform 2. Interacts with DNAJB2.TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt O70435 2 EQUAL 255 EQUAL Reactome DB_ID: 9821172 1 UniProt:O35226 Psmd4 UniProt O35226 1 EQUAL 377 EQUAL Reactome DB_ID: 9821197 1 UniProt:Q9CWH6 Psma8 Psma8 Psma7l Psma8 FUNCTION Component of the spermatoproteasome, a proteasome specifically found in testis that promotes acetylation-dependent degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis (PubMed:23706739, PubMed:31358751, PubMed:31437213). The proteasome is a protein complex that degrades unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds (Probable). Required for 20S core proteasome assembly, essential for the degradation of meiotic proteins RAD51 and RPA1 at late prophase I and the progression of meiosis I during spermatogenesis (PubMed:31358751). Localizes to the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I (PubMed:31437213).SUBUNIT Component of the outer alpha-ring of the 20S proteasome core which is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure (PubMed:23706739, PubMed:31358751). The catalytic chamber with the active sites is on the inside of the barrel (Probable). Interacts with canonical subunits of the spermatoproteasome, including proteasome activators PSME4 (also called PA200) and PSME3 (also called PA28-gamma) (PubMed:31437213). Interacts with proteasome-interacting proteins chaperones including CCT6B and CCT2, ubiquitin ligases (TRIP12, NEDD4, TRIM36 and RAD18), and ubiquitin specific proteases such as USP9X, USP34, USP5 and USP47 (PubMed:31437213). Interacts with meiotic proteins cyclin dependent kinase CDK1 and the ATPase TRIP13 as well as proteins of the synaptonemal complex SIX6OS1 and SYCE3 (PubMed:31437213).DEVELOPMENTAL STAGE In testes, expressed in spermatocytes at the pachytene stage (weakly in early pachynema and strongly in late pachynema), and its expression persisted thereafter throughout spermatogenesis.DISRUPTION PHENOTYPE Knockout mice were obtained according to the expected Mendelian ratios and showed no obvious phenotypes with respect to viability and development; however males show infertility (PubMed:31358751, PubMed:31437213). PSMA8-null spermatocytes exhibit delayed M-phase entry and are finally arrested at this stage, resulting in male infertility (PubMed:31358751, PubMed:31437213).SIMILARITY Belongs to the peptidase T1A family.CAUTION Predicted to have endopeptidase activity (By similarity). However, as it is located in the outer alpha-ring, it is suggested to lack catalytic activity and preferentially interact with regulatory complexes such as PSME4/PA200. UniProt Q9CWH6 1 EQUAL 256 EQUAL Reactome DB_ID: 9821180 1 UniProt:Q9CX56 Psmd8 UniProt Q9CX56 1 EQUAL 350 EQUAL Reactome DB_ID: 9821152 1 UniProt:P54775 UniProt P54775 1 EQUAL 418 EQUAL Reactome DB_ID: 9821178 1 UniProt:P26516 Psmd7 UniProt P26516 1 EQUAL 324 EQUAL Reactome DB_ID: 9821176 1 UniProt:Q99JI4 Psmd6 UniProt Q99JI4 1 EQUAL 389 EQUAL Reactome DB_ID: 1236800 1 UniProt:P49722 Psma2 Psma2 Psma2 Lmpc3 FUNCTION 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.TISSUE SPECIFICITY Detected in liver (at protein level).PTM Phosphorylated on tyrosine residues; which may be important for nuclear import.SIMILARITY Belongs to the peptidase T1A family. UniProt P49722 2 EQUAL 234 EQUAL Reactome DB_ID: 1236839 1 UniProt:Q9R1P0 Psma4 Psma4 Psma4 FUNCTION 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 (PubMed:16857966, PubMed:22341445).TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt Q9R1P0 1 EQUAL 261 EQUAL Reactome DB_ID: 9821158 1 UniProt:Q3TXS7 Psmd1 UniProt Q3TXS7 1 EQUAL 953 EQUAL Reactome DB_ID: 9821184 1 UniProt:P97371 Psme1 UniProt P97371 1 EQUAL 249 EQUAL Reactome DB_ID: 9821194 1 UniProt:Q5SSW2 Psme4 UniProt Q5SSW2 1 EQUAL 1843 EQUAL Reactome DB_ID: 9821144 1 UniProt:Q60692 Psmb6 Psmb6 Psmb6 Lmp19 FUNCTION 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-hydrolyzing 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.INDUCTION Up-regulated by the antioxidant dithiolethione (D3T) in liver, lung and small intestine (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt Q60692 35 EQUAL 239 EQUAL Reactome DB_ID: 9821140 1 UniProt:O09061 Psmb1 Psmb1 Psmb1 FUNCTION Non-catalytic 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 (PubMed:16857966, PubMed:22341445). Interacts with SERPINB2 (By similarity). Interacts with RFPL4A (PubMed:12525704).TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt O09061 29 EQUAL 241 EQUAL Reactome DB_ID: 9821160 1 UniProt:Q9Z2X2 Psmd10 UniProt Q9Z2X2 1 EQUAL 226 EQUAL Reactome DB_ID: 1236812 1 UniProt:P99026 Psmb4 Psmb4 Lmp3 Psmb4 FUNCTION Non-catalytic 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 (PubMed:16857966, PubMed:22341445). Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome (By similarity). Interacts with PRPF19 (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor tissues (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt P99026 46 EQUAL 264 EQUAL Reactome DB_ID: 9821188 1 UniProt:P61290 Psme3 UniProt P61290 2 EQUAL 254 EQUAL Reactome DB_ID: 9821150 1 UniProt:O88685 UniProt O88685 1 EQUAL 439 EQUAL Reactome DB_ID: 9821138 1 UniProt:Q9Z2U0 Psma7 Psma7 Psma7 FUNCTION 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 (PubMed:16857966, PubMed:22341445). PSMA7 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (By similarity). Interacts with HIF1A (By similarity). Interacts with RAB7A (By similarity). Interacts with PRKN (By similarity). Interacts with ABL1 and ABL2 (By similarity). Interacts with EMAP2 (By similarity). Interacts with MAVS (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor 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. UniProt Q9Z2U0 1 EQUAL 248 EQUAL Reactome DB_ID: 9821154 1 UniProt:P62196 UniProt P62196 2 EQUAL 406 EQUAL Reactome DB_ID: 9821166 1 UniProt:Q9WVJ2 Psmd13 UniProt Q9WVJ2 1 EQUAL 376 EQUAL Reactome DB_ID: 9821168 1 UniProt:Q8VDM4 Psmd2 UniProt Q8VDM4 1 EQUAL 908 EQUAL Reactome DB_ID: 9821162 1 UniProt:Q8BG32 Psmd11 UniProt Q8BG32 2 EQUAL 422 EQUAL Reactome DB_ID: 1236864 1 UniProt:P28063 Psmb8 Psmb8 Lmp7 Mc13 Psmb8 FUNCTION 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. May participate in the inflammatory response pathway. Required for adipocyte differentiation (PubMed:21881205, PubMed:22341445, PubMed:8066463). May be 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 (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. 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.TISSUE SPECIFICITY Detected in liver (at protein level). Expressed in spleen, thymus, lung, liver, heart and, at a very low level, in kidney. Not expressed in brain nor testis.INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Down-regulated in spleen by deoxynivalenol (DON), a mycotoxin that alters immune functions. Down-regulated by the selective inhibitor PR-957. Up-regulated by heat shock treatment. Down-regulated by EGR1 in neuronal cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.POLYMORPHISM The allele, LMP7k/LMP7s/LMPf/LMP7r/LMPcas4/LMPg7 found in strains NMRI, B10.BR, SJL, A.CA, B10.RIII, B10.cas4 and NOD may be post-translationally modified. Allele LMP7q is found in strain DBA/1J.SIMILARITY Belongs to the peptidase T1B family. UniProt P28063 73 EQUAL 276 EQUAL Reactome DB_ID: 9821164 1 UniProt:Q9D8W5 Psmd12 UniProt Q9D8W5 2 EQUAL 456 EQUAL Reactome DB_ID: 9821200 1 UniProt:Q8BG41 Psmb11 Psmb11 Psmb11 FUNCTION 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. Plays a pivotal role in development of CD8-positive T-cells.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.TISSUE SPECIFICITY Expressed exclusively in cortical thymic epithelial cells.DISRUPTION PHENOTYPE Displays defective development of CD8-positive T-cells in the thymus.SIMILARITY Belongs to the peptidase T1B family. UniProt Q8BG41 50 EQUAL 300 EQUAL Reactome DB_ID: 9821170 1 UniProt:P14685 Psmd3 UniProt P14685 1 EQUAL 534 EQUAL Reactome DB_ID: 1236853 1 UniProt:P28076 Psmb9 Psmb9 Lmp2 Ring12 Psmb9 FUNCTION 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. Contributes to NFKBIA degradation and subsequently NFKB1 generation.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. Interacts with NCOA1, NCOA2 and NCOA3.TISSUE SPECIFICITY Detected in liver (at protein level). Expressed at high levels in the thymus, spleen, lung, heart and liver. Expressed at moderate levels in the kidney.INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Up-regulated by heat shock treatment. Down-regulated by EGR1 in neuronal cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.DISRUPTION PHENOTYPE Depletion of LMP2 by RNAi suppresses expression and activities of the matrix metalloproteinase MMP2 and MMP9 by blocking the transfer of active NF-kappa-B heterodimers into the nucleus.SIMILARITY Belongs to the peptidase T1B family. UniProt P28076 21 EQUAL 219 EQUAL Reactome DB_ID: 9821186 1 UniProt:P97372 Psme2 UniProt P97372 2 EQUAL 239 EQUAL Reactome DB_ID: 9821190 1 UniProt:Q8BHL8 Psmf1 UniProt Q8BHL8 1 EQUAL 271 EQUAL Reactome DB_ID: 1236811 1 UniProt:O35955 Psmb10 Psmb10 Psmb10 Lmp10 Mecl1 FUNCTION 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. Plays a role in determining the T-cell repertoire for an antiviral T-cell response.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.TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.DISRUPTION PHENOTYPE Impaired response of cytotoxic T-lymphocyte (CTL) to dominant epitopes of lymphocytic choriomeningitis virus (LCMV).SIMILARITY Belongs to the peptidase T1B family. UniProt O35955 40 EQUAL 273 EQUAL Reactome DB_ID: 1236877 1 UniProt:Q9Z2U1 Psma5 Psma5 Psma5 FUNCTION 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 (PubMed:16857966, PubMed:22341445). PSMA5 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt Q9Z2U1 1 EQUAL 241 EQUAL Reactome Database ID Release 83 9821204 Database 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=9821204 Reactome R-MMU-68819 1 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-MMU-68819.1 GO 0004175 GO molecular function Reactome Database ID Release 83 9821205 Database 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=9821205 Reactome Database ID Release 83 9913190 Database 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=9913190 Reactome R-MMU-8850992 1 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-MMU-8850992.1 PTEN, polyubiquitinated by either NEDD4 (Wang et al. 2007), STUB1 (CHIP) (Ahmed et al. 2011), WWP2 (Maddika et al. 2011), XIAP (Van Themsche et al. 2009), MKRN1 (Lee et al. 2015) or RNF146 (Li et al. 2015), is degraded by the proteasome. inferred by electronic annotation IEA GO IEA 3.4.19.12 USP13 and OTUD3 deubiquitinate PTEN USP13 and OTUD3 deubiquitinate PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9909414 1 ubiquitinylated lysine (K48polyUb [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 29356 1 Converted from EntitySet in Reactome Reactome DB_ID: 9821134 3 Reactome DB_ID: 9839214 1 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9909420 USP13,OTUD3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity USP13 [cytosol] Otud3 [cytosol] UniProt Q5BKP2 UniProt B1AZ99 Reactome Database ID Release 83 9909421 Database 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=9909421 Reactome Database ID Release 83 9909423 Database 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=9909423 Reactome R-MMU-6807206 1 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-MMU-6807206.1 Several ubiquitin proteases deubiquitinate polyubiquitinated PTEN. USP13 and OTUD3 prolong the half-life of PTEN by preventing its proteasome-mediated degradation. Loss of USP13 or OTUD3 expression promotes AKT activation and cancer aggressiveness (Zhang et al. 2013, Yuan et al. 2015). 24270891 Pubmed 2013 Deubiquitylation and stabilization of PTEN by USP13 Zhang, Jinsong Zhang, Peijing Wei, Yongkun Piao, Hai-Long Wang, W Maddika, Subbareddy Wang, Min Chen, Dahu Sun, Yutong Hung, Mien-Chie Chen, J Ma, Li Nat. Cell Biol. 15:1486-94 26280536 Pubmed 2015 Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis Yuan, Lin Lv, Yanrong Li, Hongchang Gao, Haidong Song, Shanshan Zhang, Yuan Xing, Guichun Kong, Xiangzhen Wang, Lijing Li, Yang Zhou, Tao Gao, Daming Xiao, Zhi-Xiong Yin, Yuxin Wei, Wenyi He, Fuchu Zhang, Lingqiang Nat. Cell Biol. 17:1169-81 inferred by electronic annotation IEA GO IEA PTEN binds FRK PTEN binds FRK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9839214 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9912357 1 UniProt:Q922K9 UniProt Q922K9 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL O4'-phospho-L-tyrosine [MOD:00048] 1 EQUAL 505 EQUAL Reactome DB_ID: 9912359 1 PTEN:p-Y387-FRK [cytosol] PTEN:p-Y387-FRK Reactome DB_ID: 9839214 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9912357 1 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL 1 EQUAL 505 EQUAL Reactome Database ID Release 83 9912359 Database 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=9912359 Reactome R-MMU-8847960 1 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-MMU-8847960.1 Reactome Database ID Release 83 9912361 Database 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=9912361 Reactome R-MMU-8847968 1 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-MMU-8847968.1 FRK (RAK), a SRC family member kinase, binds PTEN. The interaction involves the SH3 domain of FRK and the C2 domain of PTEN (Yim et al. 2009). Like other SRC family members, FRK is autophosphorylated on a C-terminal tyrosine residue Y387. FRK possesses a nuclear localization signal and is found in both nucleus and the cytosol (Cance et al. 1994). 19345329 Pubmed 2009 Rak functions as a tumor suppressor by regulating PTEN protein stability and function Yim, Eun-Kyoung Peng, Guang Dai, Hui Hu, Ruozhen Li, Kaiyi Lu, Yiling Mills, Gordon B Meric-Bernstam, Funda Hennessy, Bryan T Craven, Rolf J Lin, Shiaw-Yih Cancer Cell 15:304-14 7696183 Pubmed 1994 Rak, a novel nuclear tyrosine kinase expressed in epithelial cells Cance, W G Craven, R J Bergman, M Xu, L Alitalo, K Liu, E T Cell Growth Differ. 5:1347-55 inferred by electronic annotation IEA GO IEA 2.7.10.2 FRK phosphorylates PTEN FRK phosphorylates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9912359 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9912364 1 O4'-phospho-L-tyrosine at 336 (in Homo sapiens) 336 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 9912357 1 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL 1 EQUAL 505 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9912359 GO 0004713 GO molecular function Reactome Database ID Release 83 9912365 Database 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=9912365 Reactome Database ID Release 83 9912367 Database 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=9912367 Reactome R-MMU-8847977 1 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-MMU-8847977.1 FRK tyrosine kinase (RAK) phosphorylates PTEN on tyrosine residue Y336. FRK-mediated phosphorylation inhibits NEDD4-mediated polyubiquitination and subsequent degradation of PTEN, thus increasing PTEN half-life. FRK-mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). inferred by electronic annotation IEA GO IEA 2.7.11.1 Casein kinase II phosphorylates PTEN Casein kinase II phosphorylates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9839214 1 2 EQUAL 403 EQUAL Reactome DB_ID: 113592 5 Reactome DB_ID: 29370 5 Reactome DB_ID: 9913166 1 O-phospho-L-serine at 370 (in Homo sapiens) 370 EQUAL O-phospho-L-serine at 380 (in Homo sapiens) 380 EQUAL O-phospho-L-threonine at 382 (in Homo sapiens) 382 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-threonine at 383 (in Homo sapiens) 383 EQUAL O-phospho-L-serine at 385 (in Homo sapiens) 385 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9840149 Casein kinase II [cytosol] Casein kinase II Converted from EntitySet in Reactome Reactome DB_ID: 9840147 2 CSNK2(A1:A1/A1:A2/A2:A2) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 9840133 2 UniProt:P67871 Csnk2b Csnk2b Csnk2b Ck2n FUNCTION Regulatory subunit of casein kinase II/CK2. As part of the kinase complex regulates the basal catalytic activity of the alpha subunit a constitutively active serine/threonine-protein kinase that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine (PubMed:16818610). Participates in Wnt signaling (PubMed:10806215).SUBUNIT Casein kinase II/CK2 is a tetramer composed of an alpha subunit, an alpha' subunit and two beta subunits. The beta subunit dimerization is mediated by zinc ions. Interacts with CD163. Also component of a CK2-SPT16-SSRP1 complex composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B, the complex associating following UV irradiation (By similarity). Interacts with DYNLT2. Interacts with MUSK; mediates phosphorylation of MUSK by CK2. Interacts with FGF1; this interaction is increased in the presence of FIBP, suggesting a possible cooperative interaction between CSNKB and FIBP in binding to FGF1 (By similarity).PTM Phosphorylated by alpha subunit.SIMILARITY Belongs to the casein kinase 2 subunit beta family. UniProt P67871 2 EQUAL 215 EQUAL Reactome Database ID Release 83 9840149 Database 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=9840149 Reactome R-MMU-201711 1 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-MMU-201711.1 Reactome Database ID Release 83 9840150 Database 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=9840150 Reactome Database ID Release 83 9913168 Database 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=9913168 Reactome R-MMU-8850945 1 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-MMU-8850945.1 Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. S370 and S385 are the main CK2 phosphorylation sites in PTEN (Torres and Pulido 2001, Miller et al. 2002). CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002). 11035045 Pubmed 2001 The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation Torres, J Pulido, R J. Biol. Chem. 276:993-8 12297295 Pubmed 2002 Direct identification of PTEN phosphorylation sites Miller, Susan J Lou, David Y Seldin, David C Lane, William S Neel, Benjamin G FEBS Lett. 528:145-53 inferred by electronic annotation IEA GO IEA PREX2 binds PTEN and inhibits it PREX2 binds PTEN and inhibits it This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9913172 1 UniProt:Q3LAC4 Prex2 UniProt Q3LAC4 1 EQUAL 1606 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9913174 1 PTEN, p-3S,2T-PTEN [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Pten [cytosol] phospho-Pten [cytosol] Reactome DB_ID: 9913176 1 PREX2:PTEN,p-3S,2T-PTEN [cytosol] PREX2:PTEN,p-3S,2T-PTEN Reactome DB_ID: 9913172 1 1 EQUAL 1606 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9913174 1 Reactome Database ID Release 83 9913176 Database 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=9913176 Reactome R-MMU-8850934 1 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-MMU-8850934.1 Reactome Database ID Release 83 9913178 Database 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=9913178 Reactome R-MMU-8850961 1 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-MMU-8850961.1 PREX2, a RAC1 guanine nucleotide exchange factor (GEF), binds to PTEN and inhibits its catalytic activity, resulting in enhanced PI3K/AKT signaling (Fine et al. 2009). The interaction involves the inositol polyphosphate 4-phosphatase domain and the pleckstrin homology (PH) domain of PREX2 and the PDZ binding domain, the phosphatase domain and the C2 domain of PTEN (Fine et al. 2009, Hodakoski et al. 2014). PREX2 binds both the unphosphorylated PTEN and PTEN phosphorylated at the C-terminal tail by casein kinase II, but inhibits the lipid phosphatase activity of phosphorylated PTEN only (Hodakoski et al. 2014). The GEF activity of PREX2 is not needed for PTEN inhibition (Fine et al. 2009).<p>PREX2 is frequently overexpressed in breast and prostate cancer (Fine et al. 2009) and mutated in melanoma (Berger et al. 2012). 19729658 Pubmed 2009 Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a Fine, Barry Hodakoski, Cindy Koujak, Susan Su, Tao Saal, Lao H Maurer, Matthew Hopkins, Benjamin Keniry, Megan Sulis, ML Mense, Sarah Hibshoosh, Hanina Parsons, R Science 325:1261-5 24367090 Pubmed 2014 Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis Hodakoski, Cindy Hopkins, Benjamin D Barrows, Douglas Mense, Sarah M Keniry, Megan Anderson, Karen E Kern, Philip A Hawkins, Phillip T Stephens, Len R Parsons, R Proc. Natl. Acad. Sci. U.S.A. 111:155-60 22622578 Pubmed 2012 Melanoma genome sequencing reveals frequent PREX2 mutations Berger, Michael F Hodis, Eran Heffernan, Timothy P Deribe, Yonathan Lissanu Lawrence, Michael S Protopopov, Alexei Ivanova, Elena Watson, Ian R Nickerson, Elizabeth Ghosh, Papia Zhang, Hailei Zeid, Rhamy Ren, Xiaojia Cibulskis, K Sivachenko, Andrey Y Wagle, Nikhil Sucker, Antje Sougnez, Carrie Onofrio, R Ambrogio, Lauren Auclair, Daniel Fennell, Timothy Carter, Scott L Drier, Yotam Stojanov, Petar Singer, Meredith A Voet, Douglas Jing, Rui Saksena, Gordon Barretina, Jordi Ramos, AH Pugh, Trevor J Stransky, N Parkin, Melissa Winckler, W Mahan, Scott Ardlie, Kristin Baldwin, Jennifer Wargo, Jennifer Schadendorf, Dirk Meyerson, M Gabriel, Stacey B Golub, Todd R Wagner, Stephan N Lander, Eric S Getz, G Chin, Lynda Garraway, Levi A Nature 485:502-6 inferred by electronic annotation IEA GO IEA TRIM27 binds PTEN TRIM27 binds PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9839214 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9913192 1 UniProt:Q62158 UniProt Q62158 1 EQUAL 513 EQUAL Reactome DB_ID: 9913194 1 PTEN:TRIM27 [cytosol] PTEN:TRIM27 Reactome DB_ID: 9839214 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9913192 1 1 EQUAL 513 EQUAL Reactome Database ID Release 83 9913194 Database 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=9913194 Reactome R-MMU-8851000 1 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-MMU-8851000.1 Reactome Database ID Release 83 9913196 Database 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=9913196 Reactome R-MMU-8850997 1 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-MMU-8850997.1 TRIM27 (RFP) binds PTEN. The interaction involves the C-terminal RFP domain of TRIM27 and the C-terminal tail of PTEN (Lee et al. 2013). 23419514 Pubmed 2013 RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation Lee, James T Shan, Jing Zhong, Jiayun Li, Muyang Zhou, Brenda Zhou, Amanda Parsons, R Gu, Wei Cell Res. 23:552-64 inferred by electronic annotation IEA GO IEA TRIM27 polyubiquitinates PTEN TRIM27 polyubiquitinates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9821134 3 Reactome DB_ID: 9913194 1 Reactome DB_ID: 9913199 1 ubiquitinylated lysine (K27polyUb [cytosol]) at unknown position 2 EQUAL 403 EQUAL Reactome DB_ID: 9913192 1 1 EQUAL 513 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9913194 Reactome Database ID Release 83 9913200 Database 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=9913200 Reactome Database ID Release 83 9913202 Database 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=9913202 Reactome R-MMU-8851011 1 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-MMU-8851011.1 TRIM27 (RFP) is an E3 ubiquitin ligase for PTEN. TRIM27 polyubiquitinates PTEN on multiple lysines in the C2 domain of PTEN using K27-linkage between ubiquitin molecules. TRIM27-mediated ubiquitination inhibits PTEN lipid phosphatase activity, but does not affect PTEN protein localization or stability (Lee et al. 2013). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 83 9933612 Database 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=9933612 Reactome R-MMU-8948751 1 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-MMU-8948751.1 PTEN protein stability is regulated by ubiquitin ligases, such as NEDD4, WWP2, STUB1 (CHIP), XIAP, MKRN1 and RNF146, which polyubiquitinate PTEN in response to different stimuli and thus target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Maddika et al. 2011, Ahmed et al. 2012, Lee et al. 2015, Li et al. 2015). Several ubiquitin proteases, such as USP13 and OTUD3, can remove polyubiquitin chains from PTEN and rescue it from degradation (Zhang et al. 2013, Yuan et al. 2015). TRIM27 (RFP) is an E3 ubiquitin ligase that polyubiquitinates PTEN on multiple lysines in the C2 domain of PTEN using K27 linkage between ubiquitin molecules. TRIM27 mediated ubiquitination inhibits PTEN lipid phosphatase activity, but does not affect PTEN protein localization or stability (Lee et al. 2013).<br>PTEN phosphorylation by the tyrosine kinase FRK (RAK) inhibits NEDD4 mediated polyubiquitination and subsequent degradation of PTEN, thus increasing PTEN half life. FRK mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase 2 (CK2) mediated phosphorylation of the C-terminus of PTEN on multiple serine and threonine residues increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).<br>PREX2, a RAC1 guanine nucleotide exchange factor (GEF) can binds to PTEN and inhibit its catalytic activity (Fine et al. 2009). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 83 9933610 Database 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=9933610 Reactome R-MMU-6807070 1 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-MMU-6807070.1 PTEN is regulated at the level of gene transcription, mRNA translation, localization and protein stability.<p>Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016).<p>MicroRNAs miR-26A1, miR-26A2, miR-22, miR-25, miR-302, miR-214, miR-17-5p, miR-19 and miR-205 bind PTEN mRNA and inhibit its translation into protein. These microRNAs are altered in cancer and can account for changes in PTEN levels (Meng et al. 2007, Xiao et al. 2008, Yang et al. 2008, Huse et al. 2009, Kim et al. 2010, Poliseno, Salmena, Riccardi et al. 2010, Cai et al. 2013). In addition, coding and non-coding RNAs can prevent microRNAs from binding to PTEN mRNA. These RNAs are termed competing endogenous RNAs or ceRNAs. Transcripts of the pseudogene PTENP1 and mRNAs transcribed from SERINC1, VAPA and CNOT6L genes exhibit this activity (Poliseno, Salmena, Zhang et al. 2010, Tay et al. 2011, Tay et al. 2014).<p>PTEN can translocate from the cytosol to the nucleus after undergoing monoubiquitination. PTEN's ability to localize to the nucleus contributes to its tumor suppressive role (Trotman et al. 2007). The ubiquitin protease USP7 (HAUSP) targets monoubiquitinated PTEN in the nucleus, resulting in PTEN deubiquitination and nuclear exclusion. PML, via an unknown mechanism that involves USP7- and PML-interacting protein DAXX, inhibits USP7-mediated deubiquitination of PTEN, thus promoting PTEN nuclear localization. Disruption of PML function in acute promyelocytic leukemia, through a chromosomal translocation that results in expression of a fusion protein PML-RARA, leads to aberrant PTEN localization (Song et al. 2008).<p>Several ubiquitin ligases, including NEDD4, WWP2, STUB1 (CHIP), RNF146, XIAP and MKRN1, polyubiquitinate PTEN and target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Ahmed et al. 2011, Maddika et al. 2011, Lee et al. 2015, Li et al. 2015). The ubiquitin proteases USP13 and OTUD3, frequently down-regulated in breast cancer, remove polyubiquitin chains from PTEN, thus preventing its degradation and increasing its half-life (Zhang et al. 2013, Yuan et al. 2015). The catalytic activity of PTEN is negatively regulated by PREX2 binding (Fine et al. 2009, Hodakoski et al. 2014) and TRIM27-mediated ubiquitination (Lee et al. 2013), most likely through altered PTEN conformation.<p>In addition to ubiquitination, PTEN also undergoes SUMOylation (Gonzalez-Santamaria et al. 2012, Da Silva Ferrada et al. 2013, Lang et al. 2015, Leslie et al. 2016). SUMOylation of the C2 domain of PTEN may regulate PTEN association with the plasma membrane (Shenoy et al. 2012) as well as nuclear localization of PTEN (Bassi et al. 2013, Collaud et al. 2016). PIASx-alpha, a splicing isorom of E3 SUMO-protein ligase PIAS2 has been implicated in PTEN SUMOylation (Wang et al. 2014). SUMOylation of PTEN may be regulated by activated AKT (Lin et al. 2016). Reactions describing PTEN SUMOylation will be annotated when mechanistic details become available.<p>Phosphorylation affects the stability and activity of PTEN. FRK tyrosine kinase (RAK) phosphorylates PTEN on tyrosine residue Y336, which increases PTEN half-life by inhibiting NEDD4-mediated polyubiquitination and subsequent degradation of PTEN. FRK-mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).<p>PTEN localization and activity are affected by acetylation of its lysine residues (Okumura et al. 2006, Ikenoue et al. 2008, Meng et al. 2016). PTEN can undergo oxidation, which affects its function, but the mechanism is poorly understood (Tan et al. 2015, Shen et al. 2015, Verrastro et al. 2016). 22000013 Pubmed 2011 Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs Tay, Yvonne Kats, Lev Salmena, Leonardo Weiss, Dror Tan, Shen Mynn Ala, Ugo Karreth, Florian Poliseno, Laura Provero, Paolo Di Cunto, Ferdinando Lieberman, Judy Rigoutsos, Isidore Pandolfi, Pier Paolo Cell 147:344-57 23888040 Pubmed 2013 Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress Bassi, C Ho, J Srikumar, T Dowling, R J O Gorrini, C Miller, S J Mak, T W Neel, B G Raught, B Stambolic, V Science 341:395-9 24344134 Pubmed 2014 PIASxα ligase enhances SUMO1 modification of PTEN protein as a SUMO E3 ligase Wang, Weibin Chen, Yifan Wang, Shuya Hu, Ningguang Cao, Zhengyi Wang, Wengong Tong, Tanjun Zhang, Xiaowei J. Biol. Chem. 289:3217-30 25867063 Pubmed 2016 SUMO modification of Akt regulates global SUMOylation and substrate SUMOylation specificity through Akt phosphorylation of Ubc9 and SUMO1 Lin, C H Liu, S Y Lee, E H Y Oncogene 35:595-607 19487573 Pubmed 2009 The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo Huse, Jason T Brennan, Cameron Hambardzumyan, Dolores Wee, Boyoung Pena, John Rouhanifard, Sara H Sohn-Lee, Cherin le Sage, Carlos Agami, Reuven Tuschl, Thomas Holland, Eric C Genes Dev. 23:1327-37 20388916 Pubmed 2010 Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation Poliseno, Laura Salmena, Leonardo Riccardi, Luisa Fornari, Alessandro Song, MS Hobbs, Robin M Sportoletti, Paolo Varmeh, Shorheh Egia, Ainara Fedele, Giuseppe Rameh, Lucia Loda, Massimo Pandolfi, Pier Paolo Sci Signal 3:ra29 23073177 Pubmed 2012 Membrane association of the PTEN tumor suppressor: electrostatic interaction with phosphatidylserine-containing bilayers and regulatory role of the C-terminal tail Shenoy, Siddharth S Nanda, Hirsh Lösche, Mathias J. Struct. Biol. 180:394-408 25224693 Pubmed 2015 Analysis of PTEN ubiquitylation and SUMOylation using molecular traps Lang, Valérie Aillet, Fabienne Da Silva-Ferrada, Elisa Xolalpa, Wendy Zabaleta, Lorea Rivas, Carmen Rodriguez, Manuel S Methods 77:112-8 26561776 Pubmed 2016 Reversible oxidation of phosphatase and tensin homolog (PTEN) alters its interactions with signaling and regulatory proteins Verrastro, Ivan Tveen-Jensen, Karina Woscholski, Rudiger Spickett, Corinne M Pitt, Andrew R Free Radic. Biol. Med. 90:24-34 26862215 Pubmed 2016 The PTEN protein: cellular localization and post-translational regulation Leslie, Nick R Kriplani, Nisha Hermida, Miguel A Alvarez-Garcia, Virginia Wise, Helen M Biochem. Soc. Trans. 44:273-8 18199536 Pubmed 2008 MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN Yang, Hua Kong, William He, Lili Zhao, Jian-Jun O'Donnell, Joshua D Wang, Jiawang Wenham, Robert M Coppola, Domenico Kruk, Patricia A Nicosia, Santo V Cheng, Jin Q Cancer Res. 68:425-33 17681183 Pubmed 2007 MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer Meng, Fanyin Henson, Roger Wehbe-Janek, Hania Ghoshal, Kalpana Jacob, Samson T Patel, Tushar Gastroenterology 133:647-58 23856247 Pubmed 2013 miR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer Cai, Junchao Fang, Lishan Huang, Yongbo Li, Rong Yuan, Jie Yang, Y Zhu, Xun Chen, Baixue Wu, Jueheng Li, Mengfeng Cancer Res. 73:5402-15 20577206 Pubmed 2010 A coding-independent function of gene and pseudogene mRNAs regulates tumour biology Poliseno, Laura Salmena, Leonardo Zhang, Jiangwen Carver, Brett Haveman, William J Pandolfi, Pier Paolo Nature 465:1033-8 26279303 Pubmed 2016 PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition Meng, Z Jia, L-F Gan, Y-H Oncogene 35:2333-44 16829519 Pubmed 2006 PCAF modulates PTEN activity Okumura, Koichi Mendoza, Michelle Bachoo, Robert M DePinho, Ronald A Cavenee, Webster K Furnari, Frank B J. Biol. Chem. 281:26562-8 23604351 Pubmed 2013 Analysis of SUMOylated proteins using SUMO-traps Da Silva-Ferrada, Elisa Xolalpa, Wendy Lang, Valérie Aillet, Fabienne Martin-Ruiz, Itziar de la Cruz-Herrera, Carlos F Lopitz-Otsoa, Fernando Carracedo, Arkaitz Goldenberg, SJ Rivas, Carmen England, Patrick Rodriguez, Manuel S Sci Rep 3:1690 18757404 Pubmed 2008 PTEN acetylation modulates its interaction with PDZ domain Ikenoue, T Inoki, Ken Zhao, B Guan, KL Cancer Res. 68:6908-12 20080666 Pubmed 2010 Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship Kim, Hyunsoo Huang, Wei Jiang, Xiuli Pennicooke, Brenton Park, Peter J Johnson, Mark D Proc. Natl. Acad. Sci. U.S.A. 107:2183-8 25737250 Pubmed 2015 Differential thiol oxidation of the signaling proteins Akt, PTEN or PP2A determines whether Akt phosphorylation is enhanced or inhibited by oxidative stress in C2C12 myotubes derived from skeletal muscle Tan, Pearl Lin Shavlakadze, Tea Grounds, Miranda D Arthur, Peter G Int. J. Biochem. Cell Biol. 62:72-9 26415504 Pubmed 2015 AIF inhibits tumor metastasis by protecting PTEN from oxidation Shen, Shao-Ming Guo, Meng Xiong, Zhong Yu, Yun Zhao, Xu-Yun Zhang, Fei-Fei Chen, Guo-Qiang EMBO Rep. 16:1563-80 18327259 Pubmed 2008 Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes Xiao, Changchun Srinivasan, Lakshmi Calado, Dinis Pedro Patterson, Heide Christine Zhang, Baochun Wang, Jing Henderson, Joel M Kutok, Jeffrey L Rajewsky, Klaus Nat. Immunol. 9:405-14 23013792 Pubmed 2012 Regulation of the tumor suppressor PTEN by SUMO González-Santamaría, J Campagna, M Ortega-Molina, A Marcos-Villar, L de la Cruz-Herrera, C F González, D Gallego, P Lopitz-Otsoa, F Esteban, M Rodriguez, M S Serrano, M Rivas, C Cell Death Dis 3:e393 25884169 Pubmed 2015 Lung neuroendocrine tumors: correlation of ubiquitinylation and sumoylation with nucleo-cytosolic partitioning of PTEN Collaud, Stéphane Tischler, Verena Atanassoff, Andrej Wiedl, Thomas Komminoth, Paul Oehlschlegel, Christian Weder, Walter Soltermann, A BMC Cancer 15:74 24429633 Pubmed 2014 The multilayered complexity of ceRNA crosstalk and competition Tay, Yvonne Rinn, John Pandolfi, Pier Paolo Nature 505:344-52 inferred by electronic annotation IEA GO IEA