BioPAX pathway converted from "PTEN Regulation" in the Reactome database. 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 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> LEFT-TO-RIGHT 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> SALL4:PTEN gene Reactome DB_ID: 9919846 nucleoplasm GENE ONTOLOGY GO:0005654 Ghost homologue of PTEN gene Reactome DB_ID: 9919844 Reactome Database ID Release 83 9919844 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=9919844 Reactome R-MMU-5632949 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-5632949.1 Reactome http://www.reactome.org 1 Sall4 SALL4 Q8BX22 Reactome DB_ID: 9884180 UniProt:Q8BX22 Sall4 Mus musculus NCBI Taxonomy 10090 UniProt Q8BX22 1 EQUAL 1053 EQUAL Reactome Database ID Release 83 9884180 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=9884180 Reactome R-MMU-452644 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-452644.1 1 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 NuRD complex Reactome DB_ID: 9824367 Converted from EntitySet in Reactome MTA1, MTA2, MTA3 Reactome DB_ID: 9824355 Mta1 Metastasis-associated protein MTA1 MTA1_MOUSE Reactome DB_ID: 5096466 UniProt:Q8K4B0 Mta1 Mta1 FUNCTION Transcriptional coregulator which can act as both a transcriptional corepressor and coactivator. As a part of the histone-deacetylase multiprotein complex (NuRD), regulates transcription of its targets by modifying the acetylation status of the target chromatin and cofactor accessibility to the target DNA. In conjunction with other components of NuRD, acts as a transcriptional corepressor of BRCA1, ESR1, TFF1 and CDKN1A. Acts as a transcriptional coactivator of BCAS3, PAX5 and SUMO2, independent of the NuRD complex. Stimulates the expression of WNT1 by inhibiting the expression of its transcriptional corepressor SIX3. Regulates p53-dependent and -independent DNA repair processes following genotoxic stress. Regulates the stability and function of p53/TP53 by inhibiting its ubiquitination by COP1 and MDM2 thereby regulating the p53-dependent DNA repair. Plays an important role in tumorigenesis, tumor invasion, and metastasis. Plays a role in the regulation of the circadian clock and is essential for the generation and maintenance of circadian rhythms under constant light and for normal entrainment of behavior to light-dark (LD) cycles. Positively regulates the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of its own transcription and the transcription of CRY1. Regulates deacetylation of ARNTL/BMAL1 by regulating SIRT1 expression, resulting in derepressing CRY1-mediated transcription repression. With Tfcp2l1, promotes establishment and maintenance of pluripotency in embryonic stem cells (ESCs) and inhibits endoderm differentiation (PubMed:28982712).SUBUNIT Component of the nucleosome-remodeling and histone-deacetylase multiprotein complex (NuRD). Interacts with HDAC1 and ITGB3BP/CENPR (By similarity). Binds to CSNK1G2 in the cytoplasm (PubMed:15077195). Interacts with NACC2. Interacts with EP300, TFAP2C, IFI16, TPR, UBE2I/UBC9, PIAS1, PIAS3, PIAS4, MDM2, COP1, SUMO1, SUMO2, SENP1 and SENP2 (By similarity). Interacts with ARNTL/BMAL1 and CLOCK (PubMed:24089055). Interacts with p53/TP53 (PubMed:19837670). Interacts with HDAC2 (By similarity). Interacts with SIX3; facilitates the binding of SIX3 to the core DNA motif of SIX3 promoter (PubMed:17666527). Interacts with TFCP2L1; which is indispensable for TFCP2L1-mediated self-renewal-promoting effect and endoderm-inhibiting action (PubMed:28982712). Interacts with PWWP2A and PWWP2B (PubMed:30228260, PubMed:34180153).TISSUE SPECIFICITY Widely expressed but not in skeletal muscle. Highly expressed in the brain, liver, kidney and cardiac muscle and in mammary tumors.DEVELOPMENTAL STAGE Expressed at high levels in embryonic nerve tissues, such as the brain, eyes, and spinal cord.PTM Phosphorylation by CSNK1G2/CK1 triggered by estrogen enhances corepression of estrogen receptor (ER).PTM Acetylation is essential for its transcriptional coactivator activity.PTM Sumoylation positively regulates its transcriptional corepressor activity but does not affect the protein stability. Sumoylated preferentially by SUMO2 or SUMO3 than SUMO1. Sumoylation is enhanced by PIAS1/3/4 and preferentially sumoylated by SUMO2 in the presence of PIAS1/3/4. Desumoylated by SENP1 (By similarity).PTM Ubiquitinated by COP1, which leads to proteasomal degradation.DISRUPTION PHENOTYPE Mice exhibit a disruption of the free-running period of circadian rhythms under constant light and normal entrainment of behavior to light-dark (LD) cycles.CAUTION Was originally thought to play a role in inflammatory responses both as a target and as a component of the NF-kappa-B signaling, to interact with the HDAC2, and be induced by lipopolysaccharide (LPS) (PubMed:20519513). However, this work was later retracted (PubMed:28314777). Nevertheless, the interaction with HDAC2 has been demonstrated by several publications in the human ortholog. UniProt Q8K4B0 1 EQUAL 715 EQUAL Reactome Database ID Release 83 5096466 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=5096466 Reactome R-MMU-5096466 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-5096466.1 Mta2 Metastasis-associated protein MTA2 MTA2_MOUSE Reactome DB_ID: 5096453 UniProt:Q9R190 Mta2 Mta2 Mta1l1 FUNCTION May be involved in the regulation of gene expression as repressor and activator. The repression might be related to covalent modification of histone proteins.SUBUNIT Component of the nucleosome-remodeling and histone-deacetylase multiprotein complex (NuRD) (PubMed:10444591). Interacts with HDAC7 (PubMed:10984530). Interacts with MBD3 (PubMed:12124384). Interacts with p53/TP53, MINT, PIMREG, NACC2 and ERCC6 (By similarity). Interacts with PWWP2B (PubMed:34180153). UniProt Q9R190 1 EQUAL 668 EQUAL Reactome Database ID Release 83 5096453 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=5096453 Reactome R-MMU-5096453 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-5096453.1 Mta3 MTA3 Q924K8 Reactome DB_ID: 9824353 UniProt:Q924K8 Mta3 Mta3 FUNCTION Plays a role in maintenance of the normal epithelial architecture through the repression of SNAI1 transcription in a histone deacetylase-dependent manner, and thus the regulation of E-cadherin levels. Contributes to transcriptional repression by BCL6 (By similarity).SUBUNIT Component of the nucleosome-remodeling and histone-deacetylase multiprotein complex (NuRD). Interacts with BCL6 (By similarity). Interacts with NACC2 (By similarity). Interacts with PWWP2B (PubMed:34180153).TISSUE SPECIFICITY Expressed in heart, brain, spleen, lung, liver and kidney. UniProt Q924K8 1 EQUAL 594 EQUAL Reactome Database ID Release 83 9824353 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=9824353 Reactome R-MMU-4657013 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-4657013.1 Reactome Database ID Release 83 9824355 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=9824355 Reactome R-MMU-4657019 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-4657019.1 1 Converted from EntitySet in Reactome (GATAD2A, GATAD2B) Reactome DB_ID: 9824365 Q8CHY6 Gatad2a GATAD2A Reactome DB_ID: 9824359 UniProt:Q8CHY6 Gatad2a UniProt Q8CHY6 1 EQUAL 633 EQUAL Reactome Database ID Release 83 9824359 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=9824359 Reactome R-MMU-3702077 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-3702077.1 Q8VHR5 Gatad2b GATAD2B Reactome DB_ID: 9824363 UniProt:Q8VHR5 Gatad2b UniProt Q8VHR5 1 EQUAL 593 EQUAL Reactome Database ID Release 83 9824363 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=9824363 Reactome R-MMU-3702079 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-3702079.1 Reactome Database ID Release 83 9824365 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=9824365 Reactome R-MMU-4657014 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-4657014.1 1 Hdac1:Hdac2 Reactome DB_ID: 9006136 Hdac1 Histone deacetylase 1 HDAC1_MOUSE Hdac1 Reactome DB_ID: 573340 UniProt:O09106 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 Database ID Release 83 573340 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=573340 Reactome R-MMU-573340 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-573340.1 1 Hdac2 Histone deacetylase 2 HDAC2_MOUSE Hdac2 Reactome DB_ID: 573366 UniProt:P70288 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 573366 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=573366 Reactome R-MMU-573366 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-573366.1 1 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 1 Converted from EntitySet in Reactome Mi-2 Reactome DB_ID: 9824345 CHD4 Q6PDQ2 Reactome DB_ID: 9824340 UniProt:Q6PDQ2 Chd4 Chd4 FUNCTION Component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin by deacetylating histones.SUBUNIT Central component of the nucleosome remodeling and histone deacetylase (NuRD) repressor complex (PubMed:11003653). Interacts with KLF1; the interaction depends on sumoylation of KLF1, and leads to its transcriptional repression (PubMed:17938210). Interacts with ZGPAT; the interaction is direct. Interacts with BCL6, BRD4 and PCNT. Interacts directly with IKFZ1 in the NuRD complex. Interacts with TRIM27. Part of a complex containing ATR and HDAC2. Interacts with HDAC2; the interaction is direct (By similarity). Interacts with SETX (By similarity). Interacts with HDAC1 (By similarity). Interacts with the ISWI chromatin remodeling complex component SMARCA5; the interaction is direct (By similarity). Interacts with the cohesin complex component RAD21; the interaction is direct (By similarity). Does not interact with PWWP2A and PWWP2B (PubMed:30228260, PubMed:30327463).SIMILARITY Belongs to the SNF2/RAD54 helicase family. UniProt Q6PDQ2 1 EQUAL 1912 EQUAL Reactome Database ID Release 83 9824340 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=9824340 Reactome R-MMU-3702078 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-3702078.1 Chd3 CHD3 B1AR17 Reactome DB_ID: 9824343 UniProt:B1AR17 Chd3 Chd3 UniProt B1AR17 1 EQUAL 2000 EQUAL Reactome Database ID Release 83 9824343 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=9824343 Reactome R-MMU-4657012 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-4657012.1 Reactome Database ID Release 83 9824345 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=9824345 Reactome R-MMU-4657021 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-4657021.1 1 Rbbp7 RBBP7 Q60973 Reactome DB_ID: 9824337 UniProt:Q60973 Rbbp7 Rbbp7 Rbap46 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 Database ID Release 83 9824337 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=9824337 Reactome R-MMU-212227 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-212227.1 1 Mbd3 MBD3 Q9Z2D8 Reactome DB_ID: 9824348 UniProt:Q9Z2D8 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 Database ID Release 83 9824348 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=9824348 Reactome R-MMU-4657010 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-4657010.1 1 Rbbp4 Histone-binding protein RBBP4 RBBP4_MOUSE Rbbp4 Reactome DB_ID: 573325 UniProt:Q60972 Rbbp4 Rbbp4 Rbap48 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 573325 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=573325 Reactome R-MMU-573325 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-573325.1 1 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 SALL4:NuRD:PTEN gene Reactome DB_ID: 9919850 1 SALL4:NuRD Reactome DB_ID: 9919848 1 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 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 from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT 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> MECOM:PTEN gene Reactome DB_ID: 9919858 1 Mecom MECOM P14404 Reactome DB_ID: 9919854 UniProt:P14404 Mecom UniProt P14404 1 EQUAL 1051 EQUAL Reactome Database ID Release 83 9919854 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=9919854 Reactome R-MMU-8943897 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-8943897.1 1 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 PRC1.4,PRC2 (EZH2) core Reactome DB_ID: 9919856 PRC2 (EZH2) Core Reactome DB_ID: 9842917 Ezh2 Histone-lysine N-methyltransferase EZH2 ecNumber2.1.1.43/ecNumber EZH2_MOUSE Reactome DB_ID: 5617899 UniProt:Q61188 Ezh2 Ezh2 Enx1h FUNCTION Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Displays a preference for substrates with less methylation, loses activity when progressively more methyl groups are incorporated into H3K27, H3K27me0 &gt; H3K27me1 &gt; H3K27me2. Compared to EZH1-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXA7, HOXB6 and HOXC8. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-ARNTL/BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription.SUBUNIT Component of the PRC2/EED-EZH2 complex, which includes EED, EZH2, SUZ12, RBBP4 and RBBP7 and possibly AEBP2 (By similarity). The minimum components required for methyltransferase activity of the PRC2/EED-EZH2 complex are EED, EZH2 and SUZ12 (By similarity). The PRC2 complex may also interact with DNMT1, DNMT3A, DNMT3B and PHF1 via the EZH2 subunit and with SIRT1 via the SUZ12 subunit (By similarity). Interacts with HDAC1 and HDAC2 (By similarity). Binds ATRX via the SET domain (By similarity). Interacts with PRAME (By similarity). Interacts with CDYL (By similarity). Interacts with EED. Interacts with ARNTL/BMAL1. Interacts with CLOCK and CRY1. Interacts with DNMT3L; the interaction is direct (PubMed:24074865). Interacts with EZHIP; the interaction blocks EZH2 methyltransferase activity (PubMed:31451685). 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 ARMC12 (By similarity).TISSUE SPECIFICITY Present in actively dividing cells (PubMed:19026781). Widely expressed in early embryos (PubMed:19026781). In later embryogenesis, expression restricted to central and peripheral nervous system, liver and thymus (PubMed:19026781). In adult, highest expression in spleen, testis and placenta (PubMed:19026781, PubMed:31451685). Lower levels in intestine, muscle and ovary and very low levels in brain and liver (PubMed:19026781, PubMed:31451685). No expression in heart, thyroid gland, lung and kidney (PubMed:19026781).DEVELOPMENTAL STAGE Expressed in both adult and embryo with highest levels in early embryogenesis. Expressed in the fertilized oocyte. Expression decreases during differentiation of ES cells and during senescence of MEFs. Expression increases in prostate during prostate tumor development.INDUCTION Repressed by the microRNA (miRNA) miR-26a.PTM Phosphorylated by AKT1 (By similarity). Phosphorylation by AKT1 reduces methyltransferase activity. Phosphorylation at Thr-345 by CDK1 and CDK2 promotes maintenance of H3K27me3 levels at EZH2-target loci, thus leading to epigenetic gene silencing (By similarity).PTM Sumoylated.PTM Glycosylated: O-GlcNAcylation at Ser-75 by OGT increases stability of EZH2 and facilitates the formation of H3K27me3 by the PRC2/EED-EZH2 complex.DISRUPTION PHENOTYPE Death early in development. Embryos cease development following implantation or initiate but fail to complete gastrulation.SIMILARITY Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. EZ subfamily. UniProt Q61188 1 EQUAL 746 EQUAL Reactome Database ID Release 83 5617899 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=5617899 Reactome R-MMU-5617899 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-5617899.1 1 Converted from EntitySet in Reactome RBBP4,7 Reactome DB_ID: 9842915 Reactome Database ID Release 83 9842915 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=9842915 Reactome R-MMU-4839773 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-4839773.1 1 Suz12 SUZ12 Q80U70 Reactome DB_ID: 9842913 UniProt:Q80U70 Suz12 Suz12 D11Ertd530e Kiaa0160 FUNCTION Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems (By similarity). Genes repressed by the PRC2/EED-EZH2 complex include HOXA7, HOXB6 and HOXC8.SUBUNIT 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, PubMed:20144788). Within the complex, interacts (via C2H2 zinc finger domain) with JARID2 and EPOP; JARID2 and EPOP compete for SUZ12 binding (By similarity). Also interacts with AEBP2 and PHF19 (By similarity). 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 or MTF2; PHF19 and MTF2 stabilize the dimeric structure which enhances PRC2 interaction with chromatin (By similarity). The minimum components required for methyltransferase activity of the PRC2/EZH2 complex are EED, EZH2 and SUZ12 (By similarity). The PRC2 complex may also interact with DNMT1, DNMT3A, DNMT3B and PHF1 via the EZH2 subunit and with SIRT1 via the SUZ12 subunit. Interacts with WDR77 (PubMed:16712789). Interacts with histone H1. Interacts with CDYL (By similarity). Interacts with ARNTL/BMAL1 (PubMed:23970558). Interacts with EZHIP (via C-terminal region) (By similarity). Interacts with ARMC12 (By similarity).TISSUE SPECIFICITY Expressed in embryonic stem cells.DEVELOPMENTAL STAGE Expression increases in prostate during prostate tumor development.PTM Sumoylated, probably by PIAS2.DISRUPTION PHENOTYPE Mice exhibit early embryonic lethality and defects in gastrulation accompanied by reduced methylation of 'Lys-27' of histone H3.SIMILARITY Belongs to the VEFS (VRN2-EMF2-FIS2-SU(Z)12) family. UniProt Q80U70 1 EQUAL 739 EQUAL Reactome Database ID Release 83 9842913 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=9842913 Reactome R-MMU-212217 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-212217.1 1 Eed EED Q921E6 Reactome DB_ID: 9842909 UniProt:Q921E6 Eed Eed FUNCTION Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' and 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Also recognizes 'Lys-26' trimethylated histone H1 with the effect of inhibiting PRC2 complex methyltransferase activity on nucleosomal histone H3 'Lys-27', whereas H3 'Lys-27' recognition has the opposite effect, enabling the propagation of this repressive mark (By similarity). The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems (By similarity). Genes repressed by the PRC2/EED-EZH2 complex include HOXA7, HOXB6 and HOXC8. Plays a role in X chromosome inactivation (XCI), in which one of the two X chromosomes in female mammals is transcriptionally silenced to equalize X-linked gene dosage with XY males. Required for stable maintenance of XCI in both embryonic and extraembryonic tissues. May prevent transcriptional activation of facultative heterochromatin during differentiation. Required for development of secondary trophoblast giant cells during placental development. May regulate hippocampal synaptic plasticity in the developing brain.SUBUNIT Component of the PRC2/EED-EZH2 complex, which includes EED, EZH2, SUZ12, RBBP4 and RBBP7 and possibly AEBP2 (By similarity). The minimum components required for methyltransferase activity of the PRC2/EED-EZH2 complex are EED, EZH2 and SUZ12 (By similarity). Component of the PRC2/EED-EZH1 complex, which includes EED, EZH1, SUZ12, RBBP4 and AEBP2. The PRC2 complex may also interact with DNMT1, DNMT3A, DNMT3B and PHF1 via the EZH2 subunit and with SIRT1 via the SUZ12 subunit (By similarity). Interacts with HDAC, HDAC2, histone H1 and YY1 (By similarity). May interact with ITGA4, ITGAE and ITGB7 (By similarity). Interacts with CDYL (By similarity). Interacts with EZH2. Interacts with KMT2A/MLL1 in adult brain. Interacts with ARNTL/BMAL1.TISSUE SPECIFICITY Expressed in brain, heart, kidney, liver, lung, muscle, ovary, spleen and testis. Expressed throughout the brain.DEVELOPMENTAL STAGE Maternally expressed. Expressed from 5.5 dpc, and expression remains high throughout development. Expression decreases during differentiation of embryonic stem cells (ES cells). Expression increases in prostate during prostate tumor development.INDUCTION Induced in embryonic stem cells (ES cells) by STAT3 and POU5F1.DOMAIN The WD repeat domain mediates recognition of trimethylated histone peptides at the consensus sequence Ala-Arg-Lys-Ser. This is achieved through an aromatic cage encircling the methyllysine, and involving Phe-97, Tyr-148 and Tyr-365 (By similarity).PTM Methylated. Binding to histone H1 'Lys-26' promotes mono-, di-, and trimethylation of internal lysines (By similarity).MISCELLANEOUS Mice homozygous for a null allele of this protein (Pro-196) exhibit disrupted anterior posterior patterning of the primitive streak during gastrulation and reduced numbers of trophoblast giant cells. Mice homozygous for a hypomorphic allele of this protein (Asn-193) exhibit posterior transformations along the axial skeleton and altered patterns of Hox gene expression.SIMILARITY Belongs to the WD repeat ESC family.CAUTION Was originally thought (PubMed:9234727) to interact with HNRNPK. This apparent interaction may be mediated by the translated product of the 5'-UTR sequence of the 2-hybrid clone. UniProt Q921E6 1 EQUAL 441 EQUAL Reactome Database ID Release 83 9842909 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=9842909 Reactome R-MMU-212278 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-212278.1 1 Reactome Database ID Release 83 9842917 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=9842917 Reactome R-MMU-212285 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-212285.1 PRC1.4 Reactome DB_ID: 9885278 Scmh1 SCMH1-2 Q8K214 Reactome DB_ID: 9884700 UniProt:Q8K214 Scmh1 UniProt Q8K214 1 EQUAL 660 EQUAL Reactome Database ID Release 83 9884700 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=9884700 Reactome R-MMU-389122 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-389122.1 1 Converted from EntitySet in Reactome PHC1,PHC2,PHC3 Reactome DB_ID: 9884723 PHC1 Q64028 Reactome DB_ID: 9884713 UniProt:Q64028 UniProt Q64028 1 EQUAL 1004 EQUAL Reactome Database ID Release 83 9884713 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=9884713 Reactome R-MMU-389111 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-389111.1 PHC2 Q9QWH1 Reactome DB_ID: 9884717 UniProt:Q9QWH1 UniProt Q9QWH1 1 EQUAL 858 EQUAL Reactome Database ID Release 83 9884717 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=9884717 Reactome R-MMU-389112 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-389112.1 PHC3 Q8CHP6 Reactome DB_ID: 9884721 UniProt:Q8CHP6 UniProt Q8CHP6 1 EQUAL 983 EQUAL Reactome Database ID Release 83 9884721 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=9884721 Reactome R-MMU-389116 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-389116.1 Reactome Database ID Release 83 9884723 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=9884723 Reactome R-MMU-9007200 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-9007200.1 1 Converted from EntitySet in Reactome CBX2,CBX4,CBX6,CBX8 Reactome DB_ID: 9885276 Cbx2 CBX2 P30658 Reactome DB_ID: 9884737 UniProt:P30658 Cbx2 UniProt P30658 1 EQUAL 532 EQUAL Reactome Database ID Release 83 9884737 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=9884737 Reactome R-MMU-389110 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-389110.1 Cbx4 CBX4 O55187 Reactome DB_ID: 9884740 UniProt:O55187 Cbx4 Cbx4 Pc2 FUNCTION E3 SUMO-protein ligase which facilitates SUMO1 conjugation by UBE2I. Involved in the sumoylation of HNRNPK, a p53/TP53 transcriptional coactivator, hence indirectly regulates p53/TP53 transcriptional activation resulting in p21/CDKN1A expression.FUNCTION Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development (By similarity). PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (By similarity). Binds to histone H3 trimethylated at 'Lys-9' (H3K9me3) (PubMed:16537902). Plays a role in the lineage differentiation of the germ layers in embryonic development (PubMed:22226355).PATHWAY Protein modification; protein sumoylation.SUBUNIT Interacts with SUV39H1 and HIPK2 (By similarity). Interacts with CSNK2B (By similarity). Component of a PRC1-like complex (By similarity). The composition of the PRC1 complex differs between the PRC1 complex in pluripotent embryonic stem cells containing RNF2, CBX7 and PCGF2, and the PRC1 complex in differentiating cells containing RNF2, CBX2, CBX4 and BMI1 (PubMed:22226355). Interacts with RNF2 (PubMed:22226355). Interacts (via chromodomain) with histone H3K9Me3 and single-stranded RNA (ssRNA) (PubMed:16537902). Interacts with CHTOP (PubMed:22872859). May interact with H3C15 and H3C1 (By similarity). Interacts with PRDM1 (By similarity).TISSUE SPECIFICITY Expressed in embryoid bodies.DOMAIN The polyhistidine repeat may act as a targeting signal to nuclear speckles. UniProt O55187 1 EQUAL 560 EQUAL Reactome Database ID Release 83 9884740 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=9884740 Reactome R-MMU-389118 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-389118.1 Cbx6 CBX6 Q9DBY5 Reactome DB_ID: 9885274 UniProt:Q9DBY5 Cbx6 UniProt Q9DBY5 1 EQUAL 412 EQUAL Reactome Database ID Release 83 9885274 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=9885274 Reactome R-MMU-3229071 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-3229071.1 Cbx8 CBX8 Q9QXV1 Reactome DB_ID: 9884744 UniProt:Q9QXV1 Cbx8 UniProt Q9QXV1 1 EQUAL 389 EQUAL Reactome Database ID Release 83 9884744 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=9884744 Reactome R-MMU-389117 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-389117.1 Reactome Database ID Release 83 9885276 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=9885276 Reactome R-MMU-9007203 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-9007203.1 1 Bmi1 BMI1 P25916 Reactome DB_ID: 9884704 UniProt:P25916 Bmi1 UniProt P25916 1 EQUAL 326 EQUAL Reactome Database ID Release 83 9884704 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=9884704 Reactome R-MMU-389121 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-389121.1 1 Converted from EntitySet in Reactome RING1,RNF2 RING1A,RING1B Reactome DB_ID: 9884733 Ring1 RING1 O35730 Reactome DB_ID: 9884727 UniProt:O35730 Ring1 UniProt O35730 1 EQUAL 406 EQUAL Reactome Database ID Release 83 9884727 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=9884727 Reactome R-MMU-389113 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-389113.1 Rnf2 RNF2 Q9CQJ4 Reactome DB_ID: 9884731 UniProt:Q9CQJ4 Rnf2 UniProt Q9CQJ4 1 EQUAL 336 EQUAL Reactome Database ID Release 83 9884731 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=9884731 Reactome R-MMU-389119 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-389119.1 Reactome Database ID Release 83 9884733 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=9884733 Reactome R-MMU-9007201 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-9007201.1 1 Reactome Database ID Release 83 9885278 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=9885278 Reactome R-MMU-3229073 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-3229073.1 Reactome Database ID Release 83 9919856 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=9919856 Reactome R-MMU-8943822 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-8943822.1 MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene Reactome DB_ID: 9919862 MECOM:(PRC1.4,PRC2 (EZH2) core) Reactome DB_ID: 9919860 1 1 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 1 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 LEFT-TO-RIGHT 2.7.11.1 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> Maf1 MAF1 Q9D0U6 Reactome DB_ID: 9919967 cytosol GENE ONTOLOGY GO:0005829 UniProt:Q9D0U6 Maf1 UniProt Q9D0U6 1 EQUAL 256 EQUAL Reactome Database ID Release 83 9919967 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=9919967 Reactome R-MMU-8944460 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-8944460.1 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 83 113592 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=113592 Reactome R-ALL-113592 5 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-ALL-113592.5 COMPOUND C00002 additional information MI MI:0361 3 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 83 29370 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=29370 Reactome R-ALL-29370 5 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-ALL-29370.5 COMPOUND C00008 3 Q9D0U6 phospho-Maf1 p-S60,S68,S75-MAF1 Reactome DB_ID: 9919972 60 EQUAL O-phospho-L-serine MOD MOD:00046 68 EQUAL 75 EQUAL 1 EQUAL 256 EQUAL Reactome Database ID Release 83 9919972 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=9919972 Reactome R-MMU-8944455 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-8944455.1 ACTIVATION Active mTORC1 complex Reactome DB_ID: 9831936 lysosomal membrane GENE ONTOLOGY GO:0005765 RHEB:GTP Reactome DB_ID: 9831856 RHEB Q921J2 Reactome DB_ID: 9831852 UniProt:Q921J2 UniProt Q921J2 1 EQUAL 181 EQUAL Reactome Database ID Release 83 9831852 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=9831852 Reactome R-MMU-165190 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-165190.1 1 GTP Guanosine 5'-triphosphate GTP)(4-) Reactome DB_ID: 29438 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI CHEBI:37565 Reactome Database ID Release 83 29438 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=29438 Reactome R-ALL-29438 4 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-ALL-29438.4 COMPOUND C00044 1 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 1 mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Reactome DB_ID: 9831934 mTORC1 Reactome DB_ID: 9831872 Mlst8 MLST8 Q9DCJ1 Reactome DB_ID: 9831862 UniProt:Q9DCJ1 Mlst8 UniProt Q9DCJ1 1 EQUAL 326 EQUAL Reactome Database ID Release 83 9831862 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=9831862 Reactome R-MMU-165676 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-165676.1 1 Rptor RPTOR Q8K4Q0 Reactome DB_ID: 9831870 UniProt:Q8K4Q0 Rptor UniProt Q8K4Q0 1 EQUAL 1335 EQUAL Reactome Database ID Release 83 9831870 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=9831870 Reactome R-MMU-3006727 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-3006727.1 1 Mtor MTOR Q9JLN9 Reactome DB_ID: 9831866 UniProt:Q9JLN9 Mtor UniProt Q9JLN9 1 EQUAL 2549 EQUAL Reactome Database ID Release 83 9831866 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=9831866 Reactome R-MMU-165662 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-165662.1 1 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 1 Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Reactome DB_ID: 9831932 Q8BGD6 Slc38a9 SLC38A9 Reactome DB_ID: 9831876 UniProt:Q8BGD6 Slc38a9 UniProt Q8BGD6 1 EQUAL 561 EQUAL Reactome Database ID Release 83 9831876 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=9831876 Reactome R-MMU-5215938 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-5215938.1 1 Ragulator:RagA,B:GTP:RagC,D:GDP Reactome DB_ID: 9831930 Ragulator Reactome DB_ID: 9831898 Q8CF66 Lamtor4 LAMTOR4 Reactome DB_ID: 9831892 UniProt:Q8CF66 Lamtor4 UniProt Q8CF66 1 EQUAL 99 EQUAL Reactome Database ID Release 83 9831892 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=9831892 Reactome R-MMU-5655432 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-5655432.1 1 Q9JHS3 Lamtor2 LAMTOR2 Reactome DB_ID: 9831884 UniProt:Q9JHS3 Lamtor2 UniProt Q9JHS3 1 EQUAL 125 EQUAL Reactome Database ID Release 83 9831884 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=9831884 Reactome R-MMU-5653583 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-5653583.1 1 O88653 Lamtor3 LAMTOR3 Reactome DB_ID: 9831888 UniProt:O88653 Lamtor3 UniProt O88653 1 EQUAL 124 EQUAL Reactome Database ID Release 83 9831888 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=9831888 Reactome R-MMU-5653581 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-5653581.1 1 Q9D1L9 Lamtor5 LAMTOR5 Reactome DB_ID: 9831896 UniProt:Q9D1L9 Lamtor5 UniProt Q9D1L9 1 EQUAL 91 EQUAL Reactome Database ID Release 83 9831896 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=9831896 Reactome R-MMU-5655441 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-5655441.1 1 Q9CQ22 Lamtor1 LAMTOR1 Reactome DB_ID: 9831880 UniProt:Q9CQ22 Lamtor1 UniProt Q9CQ22 2 EQUAL 161 EQUAL Reactome Database ID Release 83 9831880 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=9831880 Reactome R-MMU-5653582 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-5653582.1 1 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 1 RagA,B:GTP:RagC,D:GDP Reactome DB_ID: 9831928 Converted from EntitySet in Reactome RRAGC,RRAGD:GDP Reactome DB_ID: 9831926 RRAGC:GDP Reactome DB_ID: 9831918 GDP Guanosine 5'-diphosphate Guanosine diphosphate GDP(3-) Reactome DB_ID: 29420 GDP(3-) [ChEBI:58189] GDP(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate(3-) GDP guanosine 5'-diphosphate trianion guanosine 5'-diphosphate GDP trianion ChEBI CHEBI:58189 Reactome Database ID Release 83 29420 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=29420 Reactome R-ALL-29420 3 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-ALL-29420.3 COMPOUND C00035 1 RRAGC Q99K70 Reactome DB_ID: 9831916 UniProt:Q99K70 UniProt Q99K70 2 EQUAL 399 EQUAL Reactome Database ID Release 83 9831916 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=9831916 Reactome R-MMU-5653949 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-5653949.1 1 Reactome Database ID Release 83 9831918 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=9831918 Reactome R-MMU-5653973 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-5653973.1 RRAGD:GDP Reactome DB_ID: 9831924 RRAGD Q7TT45 Reactome DB_ID: 9831922 UniProt:Q7TT45 UniProt Q7TT45 1 EQUAL 400 EQUAL Reactome Database ID Release 83 9831922 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=9831922 Reactome R-MMU-5653953 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-5653953.1 1 1 Reactome Database ID Release 83 9831924 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=9831924 Reactome R-MMU-5653970 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-5653970.1 Reactome Database ID Release 83 9831926 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=9831926 Reactome R-MMU-5653964 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-5653964.1 1 Converted from EntitySet in Reactome RRAGA, RRAGB:GTP Reactome DB_ID: 9831912 RRAGA:GTP Reactome DB_ID: 9831904 RRAGA Q80X95 Reactome DB_ID: 9831902 UniProt:Q80X95 UniProt Q80X95 1 EQUAL 313 EQUAL Reactome Database ID Release 83 9831902 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=9831902 Reactome R-MMU-5653577 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-5653577.1 1 1 Reactome Database ID Release 83 9831904 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=9831904 Reactome R-MMU-5653978 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-5653978.1 RRAGB:GTP Reactome DB_ID: 9831910 RRAGB Q6NTA4 Reactome DB_ID: 9831908 UniProt:Q6NTA4 UniProt Q6NTA4 1 EQUAL 374 EQUAL Reactome Database ID Release 83 9831908 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=9831908 Reactome R-MMU-5653579 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-5653579.1 1 1 Reactome Database ID Release 83 9831910 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=9831910 Reactome R-MMU-5653976 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-5653976.1 Reactome Database ID Release 83 9831912 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=9831912 Reactome R-MMU-5653946 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-5653946.1 1 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 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 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 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 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 GENE ONTOLOGY GO:0004674 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity 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 LEFT-TO-RIGHT 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> Maf1 MAF1 Q9D0U6 Reactome DB_ID: 9919965 1 EQUAL 256 EQUAL Reactome Database ID Release 83 9919965 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=9919965 Reactome R-MMU-8944422 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-8944422.1 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). 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 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 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> LEFT-TO-RIGHT 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 Ub ubiquitin Reactome DB_ID: 9821134 Ubiquitin (Uba52) Reactome DB_ID: 940365 UniProt:P62984 Uba52 Uba52 Ubcep2 SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit. Interacts with UBQLN1 (via UBA domain).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family. UniProt P62984 1 EQUAL 76 EQUAL Reactome Database ID Release 83 940365 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=940365 Reactome R-MMU-940365 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-940365.1 Ubiquitin (Ubb 1) Reactome DB_ID: 940364 UniProt:P0CG49 Ubb Ubb SUBUNIT Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG49 1 EQUAL 76 EQUAL Reactome Database ID Release 83 940364 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=940364 Reactome R-MMU-940364 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-940364.1 Ubiquitin (Pps27a) Reactome DB_ID: 940370 UniProt:P62983 Rps27a Rps27a Uba80 Ubcep1 SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family. UniProt P62983 1 EQUAL 76 EQUAL Reactome Database ID Release 83 940370 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=940370 Reactome R-MMU-940370 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-940370.1 Rps27a UBB(77-152) P62983 Reactome DB_ID: 9821130 77 EQUAL 152 EQUAL Reactome Database ID Release 83 9821130 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=9821130 Reactome R-MMU-939213 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-939213.1 Ubiquitin (Ubc 1) Reactome DB_ID: 940382 UniProt:P0CG50 Ubc Ubc MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG50 1 EQUAL 76 EQUAL Reactome Database ID Release 83 940382 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=940382 Reactome R-MMU-940382 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-940382.1 Ubiquitin (Ubc 2) Reactome DB_ID: 940388 77 EQUAL 152 EQUAL Reactome Database ID Release 83 940388 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=940388 Reactome R-MMU-940388 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-940388.1 Ubiquitin (Ubc 3) Reactome DB_ID: 940362 153 EQUAL 228 EQUAL Reactome Database ID Release 83 940362 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=940362 Reactome R-MMU-940362 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-940362.1 Ubiquitin related 1 (Ubc r1) Reactome DB_ID: 940386 229 EQUAL 304 EQUAL Reactome Database ID Release 83 940386 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=940386 Reactome R-MMU-940386 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-940386.1 Ubiquitin (Ubc 4) Reactome DB_ID: 940359 305 EQUAL 380 EQUAL Reactome Database ID Release 83 940359 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=940359 Reactome R-MMU-940359 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-940359.1 Ubiquitin (Ubc 5) Reactome DB_ID: 940360 381 EQUAL 456 EQUAL Reactome Database ID Release 83 940360 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=940360 Reactome R-MMU-940360 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-940360.1 Ubiquitin (Ubc 6) Reactome DB_ID: 940384 457 EQUAL 532 EQUAL Reactome Database ID Release 83 940384 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=940384 Reactome R-MMU-940384 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-940384.1 Ubiquitin (Ubc 7) Reactome DB_ID: 940371 533 EQUAL 608 EQUAL Reactome Database ID Release 83 940371 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=940371 Reactome R-MMU-940371 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-940371.1 Ubiquitin (Ubc 8) Reactome DB_ID: 940379 609 EQUAL 684 EQUAL Reactome Database ID Release 83 940379 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=940379 Reactome R-MMU-940379 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-940379.1 Reactome Database ID Release 83 9821134 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=9821134 Reactome R-MMU-113595 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-113595.1 Pten PTEN O08586 Reactome DB_ID: 9839214 UniProt:O08586 Pten UniProt O08586 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9839214 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=9839214 Reactome R-MMU-199420 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-199420.1 Pten MonoUb-K13,K289-PTEN O08586 Reactome DB_ID: 9909383 13 EQUAL ubiquitinylated lysine MOD MOD:01148 289 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9909383 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=9909383 Reactome R-MMU-6807247 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-6807247.1 ACTIVATION Converted from EntitySet in Reactome XIAP,NEDD4 Reactome DB_ID: 9909391 XIAP Q60989 Reactome DB_ID: 9826769 UniProt:Q60989 UniProt Q60989 1 EQUAL 497 EQUAL Reactome Database ID Release 83 9826769 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=9826769 Reactome R-MMU-50849 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-50849.1 Nedd4 NEDD4 P46935 Reactome DB_ID: 9862581 UniProt:P46935 Nedd4 UniProt P46935 1 EQUAL 1319 EQUAL Reactome Database ID Release 83 9862581 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=9862581 Reactome R-MMU-975992 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-975992.1 Reactome Database ID Release 83 9909391 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=9909391 Reactome R-MMU-6807260 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-6807260.1 GENE ONTOLOGY GO:0061630 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 LEFT-TO-RIGHT 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> Pten MonoUb-K13,K289-PTEN O08586 Reactome DB_ID: 9909387 13 EQUAL 289 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9909387 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=9909387 Reactome R-MMU-6807264 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-6807264.1 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). LEFT-TO-RIGHT 3.4.19.12 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> H2O water Reactome DB_ID: 113518 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 83 113518 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=113518 Reactome R-ALL-113518 3 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-ALL-113518.3 COMPOUND C00001 Pten PTEN O08586 Reactome DB_ID: 9899592 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9899592 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=9899592 Reactome R-MMU-6807273 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-6807273.1 Converted from EntitySet in Reactome Ub Ubiquitin UBIQ_HUMAN Reactome DB_ID: 9820725 Ubiquitin (Uba52) Reactome DB_ID: 940378 1 EQUAL 76 EQUAL Reactome Database ID Release 83 940378 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=940378 Reactome R-MMU-940378 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-940378.1 Ubiquitin (Ubb 1) Reactome DB_ID: 940367 1 EQUAL 76 EQUAL Reactome Database ID Release 83 940367 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=940367 Reactome R-MMU-940367 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-940367.1 Ubiquitin (Pps27a) Reactome DB_ID: 940369 1 EQUAL 76 EQUAL Reactome Database ID Release 83 940369 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=940369 Reactome R-MMU-940369 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-940369.1 Rps27a UBB(77-152) P62983 Reactome DB_ID: 9820720 77 EQUAL 152 EQUAL Reactome Database ID Release 83 9820720 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=9820720 Reactome R-MMU-939870 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-939870.1 Ubiquitin (Ubc 1) Reactome DB_ID: 940376 1 EQUAL 76 EQUAL Reactome Database ID Release 83 940376 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=940376 Reactome R-MMU-940376 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-940376.1 Ubiquitin (Ubc 2) Reactome DB_ID: 940374 77 EQUAL 152 EQUAL Reactome Database ID Release 83 940374 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=940374 Reactome R-MMU-940374 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-940374.1 Ubiquitin (Ubc 3) Reactome DB_ID: 940381 153 EQUAL 228 EQUAL Reactome Database ID Release 83 940381 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=940381 Reactome R-MMU-940381 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-940381.1 Ubiquitin related 1 (Ubc r1) Reactome DB_ID: 940391 229 EQUAL 304 EQUAL Reactome Database ID Release 83 940391 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=940391 Reactome R-MMU-940391 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-940391.1 Ubiquitin (Ubc 4) Reactome DB_ID: 940387 305 EQUAL 380 EQUAL Reactome Database ID Release 83 940387 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=940387 Reactome R-MMU-940387 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-940387.1 Ubiquitin (Ubc 5) Reactome DB_ID: 940368 381 EQUAL 456 EQUAL Reactome Database ID Release 83 940368 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=940368 Reactome R-MMU-940368 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-940368.1 Ubiquitin (Ubc 6) Reactome DB_ID: 940389 457 EQUAL 532 EQUAL Reactome Database ID Release 83 940389 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=940389 Reactome R-MMU-940389 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-940389.1 Ubiquitin (Ubc 7) Reactome DB_ID: 940390 533 EQUAL 608 EQUAL Reactome Database ID Release 83 940390 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=940390 Reactome R-MMU-940390 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-940390.1 Ubiquitin (Ubc 8) Reactome DB_ID: 940375 609 EQUAL 684 EQUAL Reactome Database ID Release 83 940375 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=940375 Reactome R-MMU-940375 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-940375.1 Reactome Database ID Release 83 9820725 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=9820725 Reactome R-MMU-68524 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-68524.1 2 ACTIVATION Usp7 USP7 Q6A4J8 Reactome DB_ID: 9885022 UniProt:Q6A4J8 Usp7 UniProt Q6A4J8 1 EQUAL 1102 EQUAL Reactome Database ID Release 83 9885022 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=9885022 Reactome R-MMU-3215278 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-3215278.1 GENE ONTOLOGY GO:0004843 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 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 PML Q60953 Reactome DB_ID: 9884584 UniProt:Q60953 UniProt Q60953 1 EQUAL 882 EQUAL Reactome Database ID Release 83 9884584 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=9884584 Reactome R-MMU-1031706 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-1031706.1 LEFT-TO-RIGHT 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 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). 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). 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> LEFT-TO-RIGHT 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> 3 Pten PolyUb-PTEN O08586 Reactome DB_ID: 9909402 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9909402 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=9909402 Reactome R-MMU-6807280 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-6807280.1 ACTIVATION Converted from EntitySet in Reactome NEDD4,STUB1,WWP2 and XIAP Reactome DB_ID: 9909408 Stub1 STUB1 Q9WUD1 Reactome DB_ID: 9862559 UniProt:Q9WUD1 Stub1 UniProt Q9WUD1 1 EQUAL 303 EQUAL Reactome Database ID Release 83 9862559 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=9862559 Reactome R-MMU-975970 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-975970.1 Wwp2 WWP2 Q9DBH0 Reactome DB_ID: 9909406 UniProt:Q9DBH0 Wwp2 UniProt Q9DBH0 1 EQUAL 870 EQUAL Reactome Database ID Release 83 9909406 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=9909406 Reactome R-MMU-6807279 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-6807279.1 Reactome Database ID Release 83 9909408 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=9909408 Reactome R-MMU-6807286 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-6807286.1 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 LEFT-TO-RIGHT 2.7.11.1 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> Mkrn1 MKRN1 Q9QXP6 Reactome DB_ID: 9862899 UniProt:Q9QXP6 Mkrn1 UniProt Q9QXP6 1 EQUAL 482 EQUAL Reactome Database ID Release 83 9862899 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=9862899 Reactome R-MMU-976042 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-976042.1 Q9QXP6 phospho-Mkrn1 p-S109-MKRN1 Reactome DB_ID: 9920165 109 EQUAL 1 EQUAL 482 EQUAL Reactome Database ID Release 83 9920165 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=9920165 Reactome R-MMU-8948758 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-8948758.1 ACTIVATION activeUnit: #Protein96 Converted from EntitySet in Reactome Active AKT p-T,p-S-AKT Reactome DB_ID: 9838182 P31750 phospho-p-T308,S473-AKT1 Reactome DB_ID: 9838174 UniProt:P31750 Akt1 Akt1 Akt Rac FUNCTION AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:11882383, PubMed:21620960, PubMed:21432781). AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (PubMed:9415393). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (PubMed:11579209). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (PubMed:11994271). AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity (PubMed:22057101). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (PubMed:22057101). AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating the TORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. Also regulates the TORC1 signaling pathway by catalyzing phosphorylation of CASTOR1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1 (By similarity). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (PubMed:10454575). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth (By similarity). AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (PubMed:19778506). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) (PubMed:11282895, PubMed:18288188). AKT mediates the antiapoptotic effects of IGF-I (PubMed:11282895). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (By similarity). May be involved in the regulation of the placental development (PubMed:12783884). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53. Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility. Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation. Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (By similarity). Phosphorylates PCK1 at 'Ser-90', reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor (By similarity). Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity (PubMed:32228865). Acts as a negative regulator of the cGAS-STING pathway by mediating phosphorylation of CGAS during mitosis, leading to its inhibition (PubMed:26440888).ACTIVITY REGULATION Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation.SUBUNIT Interacts with and phosphorylated by PDPK1 (By similarity). Interacts with AGAP2 (isoform 2/PIKE-A); the interaction occurs in the presence of guanine nucleotides. Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A and TCL1B. Interacts with CDKN1B; the interaction phosphorylates CDKN1B promoting 14-3-3 binding and cell-cycle progression. Interacts with MAP3K5 and TRAF6. Interacts with BAD, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with RAF1 (By similarity). Interacts (via the C-terminus) with CCDC88A (via its C-terminus) and THEM4 (via its C-terminus). Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE-binding. Interacts with KCTD20 (PubMed:24156551). Interacts with BTBD10 (PubMed:18160256). Interacts with PA2G4 (By similarity). Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation (By similarity). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (By similarity). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529, PubMed:20189988). Forms a complex with WDFY2 and FOXO1 (PubMed:18388859). Interacts with FAM168A (By similarity). Interacts with SYAP1 (via phosphorylated form and BSD domain); this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1 (PubMed:23300339). Interacts with PKHM3 (PubMed:19028694). Interacts with FKBP5/FKBP51; promoting interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1 (By similarity). Interacts with TMEM175; leading to formation of the lysoK(GF) complex (By similarity).TISSUE SPECIFICITY Widely expressed. Low levels found in liver with slightly higher levels present in thymus and testis.DEVELOPMENTAL STAGE Expressed in trophoblast and vessel endothelial cells of the placenta and in the brain at 14.5 dpc (at protein level).DOMAIN Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction.DOMAIN The AGC-kinase C-terminal mediates interaction with THEM4.PTM O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1 (By similarity). O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site (PubMed:18570920, PubMed:18288188).PTM Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity. Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA. This phosphorylated form localizes to the plasma membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation. Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1. Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1. Ser-473 phosphorylation is enhanced by signaling through activated FLT3. Ser-473 is dephosphorylated by PHLPP (By similarity). Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase. The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase. Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (By similarity).PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation. When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. Also ubiquitinated by TRIM13 leading to its proteasomal degradation. Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome. Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation.PTM Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition (By similarity).PTM Cleavage by caspase-3/CASP3 (PubMed:12124386). Cleaved at the caspase-3 consensus site Asp-462 during apoptosis, resulting in down-regulation of the AKT signaling pathway and decreased cell survival (PubMed:12124386).DISRUPTION PHENOTYPE Show fetal growth impairment and reduced vascularization in the placenta; majority of pups died within 10 days.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain. UniProt P31750 308 EQUAL O-phospho-L-threonine MOD MOD:00047 473 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 83 9838174 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=9838174 Reactome R-MMU-198356 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-198356.1 Q60823 phospho-p-T309,S474-AKT2 Reactome DB_ID: 9827336 UniProt:Q60823 Akt2 Akt2 FUNCTION AKT2 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinases, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development.FUNCTION One of the few specific substrates of AKT2 identified so far is PITX2. Phosphorylation of PITX2 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1. AKT2 seems also to be the principal isoform responsible of the regulation of glucose uptake. Phosphorylates C2CD5 on 'Ser-197' during insulin-stimulated adipocytes. AKT2 is also specifically involved in skeletal muscle differentiation, one of its substrates in this process being ANKRD2. Phosphorylates CLK2 on 'Thr-343'.ACTIVITY REGULATION Two specific sites, one in the kinase domain (Thr-309) and the other in the C-terminal regulatory region (Ser-474), need to be phosphorylated for its full activation.SUBUNIT Interacts (via PH domain) with MTCP1, TCL1A and TCL1B. Interacts with CLK2, PBH2 and TRAF6. Interacts (when phosphorylated) with CLIP3, the interaction promotes cell membrane localization (By similarity). Interacts with BTBD10 (PubMed:18160256). Interacts with KCTD20 (PubMed:24156551). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529, PubMed:20189988).DOMAIN Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PIK3CA) results in its targeting to the plasma membrane.PTM Phosphorylation on Thr-309 and Ser-474 is required for full activity.PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT2 ubiquitination. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome (By similarity).PTM O-GlcNAcylation at Thr-306 and Thr-313 inhibits activating phosphorylation at Thr-309 via disrupting the interaction between AKT and PDK1.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain. UniProt Q60823 309 EQUAL 474 EQUAL 1 EQUAL 481 EQUAL Reactome Database ID Release 83 9827336 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=9827336 Reactome R-MMU-202062 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-202062.1 Q9WUA6 phospho-p-T305,S472-AKT3 Reactome DB_ID: 9838180 UniProt:Q9WUA6 UniProt Q9WUA6 305 EQUAL 472 EQUAL 1 EQUAL 479 EQUAL Reactome Database ID Release 83 9838180 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=9838180 Reactome R-MMU-3009367 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-3009367.1 Reactome Database ID Release 83 9838182 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=9838182 Reactome R-MMU-202074 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-202074.1 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 GENE ONTOLOGY GO:0043491 gene ontology term for cellular process MI MI:0359 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 LEFT-TO-RIGHT 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> 3 Pten K48polyUb-K289-PTEN O08586 Reactome DB_ID: 9909414 289 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9909414 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=9909414 Reactome R-MMU-8948777 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-8948777.1 ACTIVATION 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). LEFT-TO-RIGHT 2.4.2.30 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> NAD NAD+ NAD(+) Nicotinamide adenine dinucleotide DPN Diphosphopyridine nucleotide Reactome DB_ID: 29360 NAD(1-) [ChEBI:57540] NAD(1-) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD(+) NAD anion ChEBI CHEBI:57540 Reactome Database ID Release 83 29360 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=29360 Reactome R-ALL-29360 5 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-ALL-29360.5 COMPOUND C00003 3 O08586 phospho-Pten RibC-E40,E150,D326-PTEN Reactome DB_ID: 9920172 40 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue MOD MOD:00752 150 EQUAL 326 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9920172 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=9920172 Reactome R-MMU-8948798 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-8948798.1 NAM nicotinamide Reactome DB_ID: 197277 nicotinamide [ChEBI:17154] nicotinamide ChEBI CHEBI:17154 Reactome Database ID Release 83 197277 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=197277 Reactome R-ALL-197277 3 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-ALL-197277.3 COMPOUND C00153 3 ACTIVATION Converted from EntitySet in Reactome TNKS1/2 Reactome DB_ID: 9886656 TNKS2 Q3UES3 Reactome DB_ID: 9886650 UniProt:Q3UES3 UniProt Q3UES3 1 EQUAL 1166 EQUAL Reactome Database ID Release 83 9886650 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=9886650 Reactome R-MMU-3640824 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-3640824.1 TNKS Q6PFX9 Reactome DB_ID: 9886654 UniProt:Q6PFX9 UniProt Q6PFX9 1 EQUAL 1327 EQUAL Reactome Database ID Release 83 9886654 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=9886654 Reactome R-MMU-3640825 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-3640825.1 Reactome Database ID Release 83 9886656 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=9886656 Reactome R-MMU-3640826 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-3640826.1 GENE ONTOLOGY GO:0003950 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 LEFT-TO-RIGHT 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> 9 O08586 phospho-Pten PolyUb-K324,K344,K349-RibC-E40,E150,D326-PTEN Reactome DB_ID: 9913186 342 EQUAL 344 EQUAL 349 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9913186 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=9913186 Reactome R-MMU-8948841 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-8948841.1 ACTIVATION RNF146 Q9CZW6 Reactome DB_ID: 9886636 UniProt:Q9CZW6 UniProt Q9CZW6 1 EQUAL 359 EQUAL Reactome Database ID Release 83 9886636 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=9886636 Reactome R-MMU-3640827 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-3640827.1 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). LEFT-TO-RIGHT 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 PolyUb-PTEN, K48polyUb-K289-PTEN, PolyUb-K324,K344,K349-RibC-E40,E150,D326-PTEN Reactome DB_ID: 9913188 Reactome Database ID Release 83 9913188 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=9913188 Reactome R-MMU-8948842 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-8948842.1 3 ACTIVATION 26S proteasome Reactome DB_ID: 9821204 Ghost homologue of SEM1 Reactome DB_ID: 9821202 Reactome Database ID Release 83 9821202 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=9821202 Reactome R-MMU-8866674 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-8866674.1 1 PSMB5 O55234 Reactome DB_ID: 9821142 UniProt:O55234 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 Database ID Release 83 9821142 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=9821142 Reactome R-MMU-68753 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-68753.1 1 Psmd9 PSMD9 Q9CR00 Reactome DB_ID: 9821182 UniProt:Q9CR00 Psmd9 UniProt Q9CR00 1 EQUAL 223 EQUAL Reactome Database ID Release 83 9821182 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=9821182 Reactome R-MMU-68810 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-68810.1 1 Psma6 Proteasome subunit alpha type-6 PSA6_MOUSE Psma6 Reactome DB_ID: 1236823 UniProt:Q9QUM9 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 Database ID Release 83 1236823 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=1236823 Reactome R-MMU-1236823 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-1236823.1 1 Psmb3 Proteasome subunit beta type-3 PSB3_MOUSE Psmb3 Reactome DB_ID: 1236795 UniProt:Q9R1P1 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 Database ID Release 83 1236795 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=1236795 Reactome R-MMU-1236795 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-1236795.1 1 Psmb7 Proteasome subunit beta type-7 PSB7_MOUSE Psmb7 Reactome DB_ID: 1236775 UniProt:P70195 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 Database ID Release 83 1236775 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=1236775 Reactome R-MMU-1236775 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-1236775.1 1 PSMC2 P46471 Reactome DB_ID: 9821148 UniProt:P46471 UniProt P46471 2 EQUAL 433 EQUAL Reactome Database ID Release 83 9821148 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=9821148 Reactome R-MMU-68771 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-68771.1 1 PSMC6 P62334 Reactome DB_ID: 9821156 UniProt:P62334 UniProt P62334 1 EQUAL 389 EQUAL Reactome Database ID Release 83 9821156 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=9821156 Reactome R-MMU-68783 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-68783.1 1 Psmb2 Proteasome subunit beta type-2 PSB2_MOUSE Psmb2 Reactome DB_ID: 1236756 UniProt:Q9R1P3 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 Database ID Release 83 1236756 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=1236756 Reactome R-MMU-1236756 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-1236756.1 1 PSMD14 O35593 Reactome DB_ID: 9821136 UniProt:O35593 UniProt O35593 1 EQUAL 310 EQUAL Reactome Database ID Release 83 9821136 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=9821136 Reactome R-MMU-68722 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-68722.1 1 Psma1 Proteasome subunit alpha type-1 PSA1_MOUSE Psma1 Reactome DB_ID: 1236802 UniProt:Q9R1P4 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 Database ID Release 83 1236802 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=1236802 Reactome R-MMU-1236802 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-1236802.1 1 PSMC1 P62192 Reactome DB_ID: 9821146 UniProt:P62192 UniProt P62192 2 EQUAL 440 EQUAL Reactome Database ID Release 83 9821146 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=9821146 Reactome R-MMU-68768 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-68768.1 1 Psmd5 PSMD5 Q8BJY1 Reactome DB_ID: 9821174 UniProt:Q8BJY1 Psmd5 UniProt Q8BJY1 2 EQUAL 504 EQUAL Reactome Database ID Release 83 9821174 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=9821174 Reactome R-MMU-68802 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-68802.1 1 Psma3 Proteasome subunit alpha type-3 PSA3_MOUSE Psma3 Reactome DB_ID: 1236868 UniProt:O70435 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 Database ID Release 83 1236868 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=1236868 Reactome R-MMU-1236868 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-1236868.1 1 Psmd4 PSMD4 O35226 Reactome DB_ID: 9821172 UniProt:O35226 Psmd4 UniProt O35226 1 EQUAL 377 EQUAL Reactome Database ID Release 83 9821172 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=9821172 Reactome R-MMU-68800 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-68800.1 1 Psma8 PSMA8 Q9CWH6 Reactome DB_ID: 9821197 UniProt:Q9CWH6 Psma8 Psma8 Psma7l 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 Database ID Release 83 9821197 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=9821197 Reactome R-MMU-947610 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-947610.1 1 Psmd8 PSMD8 Q9CX56 Reactome DB_ID: 9821180 UniProt:Q9CX56 Psmd8 UniProt Q9CX56 1 EQUAL 350 EQUAL Reactome Database ID Release 83 9821180 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=9821180 Reactome R-MMU-68808 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-68808.1 1 PSMC4 P54775 Reactome DB_ID: 9821152 UniProt:P54775 UniProt P54775 1 EQUAL 418 EQUAL Reactome Database ID Release 83 9821152 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=9821152 Reactome R-MMU-68777 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-68777.1 1 Psmd7 PSMD7 P26516 Reactome DB_ID: 9821178 UniProt:P26516 Psmd7 UniProt P26516 1 EQUAL 324 EQUAL Reactome Database ID Release 83 9821178 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=9821178 Reactome R-MMU-68806 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-68806.1 1 Psmd6 PSMD6 Q99JI4 Reactome DB_ID: 9821176 UniProt:Q99JI4 Psmd6 UniProt Q99JI4 1 EQUAL 389 EQUAL Reactome Database ID Release 83 9821176 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=9821176 Reactome R-MMU-68804 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-68804.1 1 Psma2 Proteasome subunit alpha type-2 PSA2_MOUSE Psma2 Reactome DB_ID: 1236800 UniProt:P49722 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 Database ID Release 83 1236800 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=1236800 Reactome R-MMU-1236800 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-1236800.1 1 Psma4 Proteasome subunit alpha type-4 PSA4_MOUSE Psma4 Reactome DB_ID: 1236839 UniProt:Q9R1P0 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 Database ID Release 83 1236839 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=1236839 Reactome R-MMU-1236839 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-1236839.1 1 Psmd1 PSMD1 Q3TXS7 Reactome DB_ID: 9821158 UniProt:Q3TXS7 Psmd1 UniProt Q3TXS7 1 EQUAL 953 EQUAL Reactome Database ID Release 83 9821158 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=9821158 Reactome R-MMU-68786 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-68786.1 1 Psme1 PSME1 P97371 Reactome DB_ID: 9821184 UniProt:P97371 Psme1 UniProt P97371 1 EQUAL 249 EQUAL Reactome Database ID Release 83 9821184 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=9821184 Reactome R-MMU-68812 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-68812.1 1 Psme4 PSME4 Q5SSW2 Reactome DB_ID: 9821194 UniProt:Q5SSW2 Psme4 UniProt Q5SSW2 1 EQUAL 1843 EQUAL Reactome Database ID Release 83 9821194 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=9821194 Reactome R-MMU-947606 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-947606.1 1 Psmb6 PSMB6 Q60692 Reactome DB_ID: 9821144 UniProt:Q60692 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 Database ID Release 83 9821144 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=9821144 Reactome R-MMU-68756 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-68756.1 1 Psmb1 PSMB1 O09061 Reactome DB_ID: 9821140 UniProt:O09061 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 Database ID Release 83 9821140 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=9821140 Reactome R-MMU-68738 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-68738.1 1 Psmd10 PSMD10 Q9Z2X2 Reactome DB_ID: 9821160 UniProt:Q9Z2X2 Psmd10 UniProt Q9Z2X2 1 EQUAL 226 EQUAL Reactome Database ID Release 83 9821160 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=9821160 Reactome R-MMU-68788 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-68788.1 1 Psmb4 Proteasome subunit beta type-4 PSB4_MOUSE Psmb4 Reactome DB_ID: 1236812 UniProt:P99026 Psmb4 Psmb4 Lmp3 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 Database ID Release 83 1236812 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=1236812 Reactome R-MMU-1236812 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-1236812.1 1 Psme3 PSME3 P61290 Reactome DB_ID: 9821188 UniProt:P61290 Psme3 UniProt P61290 2 EQUAL 254 EQUAL Reactome Database ID Release 83 9821188 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=9821188 Reactome R-MMU-68816 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-68816.1 1 PSMC3 O88685 Reactome DB_ID: 9821150 UniProt:O88685 UniProt O88685 1 EQUAL 439 EQUAL Reactome Database ID Release 83 9821150 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=9821150 Reactome R-MMU-68774 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-68774.1 1 Psma7 PSMA7 Q9Z2U0 Reactome DB_ID: 9821138 UniProt:Q9Z2U0 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 Database ID Release 83 9821138 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=9821138 Reactome R-MMU-68736 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-68736.1 1 PSMC5 P62196 Reactome DB_ID: 9821154 UniProt:P62196 UniProt P62196 2 EQUAL 406 EQUAL Reactome Database ID Release 83 9821154 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=9821154 Reactome R-MMU-68780 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-68780.1 1 Psmd13 PSMD13 Q9WVJ2 Reactome DB_ID: 9821166 UniProt:Q9WVJ2 Psmd13 UniProt Q9WVJ2 1 EQUAL 376 EQUAL Reactome Database ID Release 83 9821166 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=9821166 Reactome R-MMU-68794 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-68794.1 1 Psmd2 PSMD2 Q8VDM4 Reactome DB_ID: 9821168 UniProt:Q8VDM4 Psmd2 UniProt Q8VDM4 1 EQUAL 908 EQUAL Reactome Database ID Release 83 9821168 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=9821168 Reactome R-MMU-68796 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-68796.1 1 Psmd11 PSMD11 Q8BG32 Reactome DB_ID: 9821162 UniProt:Q8BG32 Psmd11 UniProt Q8BG32 2 EQUAL 422 EQUAL Reactome Database ID Release 83 9821162 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=9821162 Reactome R-MMU-68790 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-68790.1 1 Psmb8 Proteasome subunit beta type-8 PSB8_MOUSE Psmb8 Reactome DB_ID: 1236864 UniProt:P28063 Psmb8 Psmb8 Lmp7 Mc13 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 Database ID Release 83 1236864 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=1236864 Reactome R-MMU-1236864 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-1236864.1 1 Psmd12 PSMD12 Q9D8W5 Reactome DB_ID: 9821164 UniProt:Q9D8W5 Psmd12 UniProt Q9D8W5 2 EQUAL 456 EQUAL Reactome Database ID Release 83 9821164 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=9821164 Reactome R-MMU-68792 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-68792.1 1 Psmb11 PSMB11 Q8BG41 Reactome DB_ID: 9821200 UniProt:Q8BG41 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 Database ID Release 83 9821200 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=9821200 Reactome R-MMU-947607 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-947607.1 1 Psmd3 PSMD3 P14685 Reactome DB_ID: 9821170 UniProt:P14685 Psmd3 UniProt P14685 1 EQUAL 534 EQUAL Reactome Database ID Release 83 9821170 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=9821170 Reactome R-MMU-68798 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-68798.1 1 Psmb9 Proteasome subunit beta type-9 PSB9_MOUSE Psmb9 Reactome DB_ID: 1236853 UniProt:P28076 Psmb9 Psmb9 Lmp2 Ring12 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 Database ID Release 83 1236853 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=1236853 Reactome R-MMU-1236853 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-1236853.1 1 Psme2 PSME2 P97372 Reactome DB_ID: 9821186 UniProt:P97372 Psme2 UniProt P97372 2 EQUAL 239 EQUAL Reactome Database ID Release 83 9821186 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=9821186 Reactome R-MMU-68814 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-68814.1 1 Psmf1 PSMF1 Q8BHL8 Reactome DB_ID: 9821190 UniProt:Q8BHL8 Psmf1 UniProt Q8BHL8 1 EQUAL 271 EQUAL Reactome Database ID Release 83 9821190 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=9821190 Reactome R-MMU-68818 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-68818.1 1 Psmb10 Proteasome subunit beta type-10 PSB10_MOUSE Psmb10 Reactome DB_ID: 1236811 UniProt:O35955 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 Database ID Release 83 1236811 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=1236811 Reactome R-MMU-1236811 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-1236811.1 1 Psma5 Proteasome subunit alpha type-5 PSA5_MOUSE Psma5 Reactome DB_ID: 1236877 UniProt:Q9Z2U1 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 1236877 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=1236877 Reactome R-MMU-1236877 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-1236877.1 1 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 GENE ONTOLOGY GO:0004175 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. LEFT-TO-RIGHT 3.4.19.12 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> H2O water Reactome DB_ID: 29356 Reactome Database ID Release 83 29356 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=29356 Reactome R-ALL-29356 5 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-ALL-29356.5 COMPOUND C00001 3 ACTIVATION Converted from EntitySet in Reactome USP13,OTUD3 Reactome DB_ID: 9909420 USP13 Q5BKP2 Reactome DB_ID: 9902508 UniProt:Q5BKP2 UniProt Q5BKP2 1 EQUAL 863 EQUAL Reactome Database ID Release 83 9902508 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=9902508 Reactome R-MMU-6781893 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-6781893.1 Otud3 OTUD3 B1AZ99 Reactome DB_ID: 9909418 UniProt:B1AZ99 Otud3 UniProt B1AZ99 1 EQUAL 398 EQUAL Reactome Database ID Release 83 9909418 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=9909418 Reactome R-MMU-8873955 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-8873955.1 Reactome Database ID Release 83 9909420 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=9909420 Reactome R-MMU-8948849 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-8948849.1 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 LEFT-TO-RIGHT 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> Q922K9 phospho-p-Y387-FRK Reactome DB_ID: 9912357 UniProt:Q922K9 UniProt Q922K9 387 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 1 EQUAL 505 EQUAL Reactome Database ID Release 83 9912357 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=9912357 Reactome R-MMU-8847965 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-8847965.1 PTEN:p-Y387-FRK Reactome DB_ID: 9912359 1 1 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 LEFT-TO-RIGHT 2.7.10.2 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> O08586 phospho-Pten p-Y336-PTEN Reactome DB_ID: 9912364 336 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9912364 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=9912364 Reactome R-MMU-8847980 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-8847980.1 ACTIVATION activeUnit: #Protein155 GENE ONTOLOGY GO:0004713 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). LEFT-TO-RIGHT 2.7.11.1 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> 5 5 O08586 phospho-Pten p-3S,2T-PTEN Reactome DB_ID: 9913166 370 EQUAL 380 EQUAL 382 EQUAL 383 EQUAL 385 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9913166 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=9913166 Reactome R-MMU-8850936 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-8850936.1 ACTIVATION Casein kinase II Reactome DB_ID: 9840149 Converted from EntitySet in Reactome CSNK2(A1:A1/A1:A2/A2:A2) CKII alpha catalytic subunit Reactome DB_ID: 9840147 CSNK2A1 dimer Reactome DB_ID: 9840138 Q60737 CSNK2A1 Reactome DB_ID: 9840136 UniProt:Q60737 Csnk2a1 Csnk2a1 Ckiia FUNCTION Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine (By similarity). Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection (By similarity). May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response (By similarity). During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage (By similarity). Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation (By similarity). Can also negatively regulate apoptosis (PubMed:18467326). Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3 (PubMed:18467326). Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8 (PubMed:18467326). Phosphorylates YY1, protecting YY1 from cleavage by CASP7 during apoptosis (By similarity). Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV (By similarity). Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, ATF4, SRF, MAX, JUN, FOS, MYC and MYB (By similarity). Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function (By similarity). Mediates sequential phosphorylation of FNIP1, promoting its gradual interaction with Hsp90, leading to activate both kinase and non-kinase client proteins of Hsp90 (By similarity). Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1 (PubMed:10806215). Acts as an ectokinase that phosphorylates several extracellular proteins (By similarity). During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV (By similarity). Phosphorylates PML at 'Ser-565' and primes it for ubiquitin-mediated degradation (By similarity). Plays an important role in the circadian clock function by phosphorylating ARNTL/BMAL1 at 'Ser-90' which is pivotal for its interaction with CLOCK and which controls CLOCK nuclear entry (By similarity).ACTIVITY REGULATION Constitutively active protein kinase whose activity is not directly affected by phosphorylation. Seems to be regulated by level of expression and localization (By similarity).SUBUNIT Heterotetramer composed of two catalytic subunits (alpha chain and/or alpha' chain) and two regulatory subunits (beta chains). The tetramer can exist as a combination of 2 alpha/2 beta, 2 alpha'/2 beta or 1 alpha/1 alpha'/2 beta subunits. Also part of a CK2-SPT16-SSRP1 complex composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B, which forms following UV irradiation (By similarity). Interacts with RNPS1 (By similarity). Interacts with SNAI1 (PubMed:19923321). Interacts with PML and CCAR2 (By similarity).PTM Phosphorylated at Thr-344, Thr-360, Ser-362 and Ser-370 by CDK1 in prophase and metaphase and dephosphorylated during anaphase. Phosphorylation does not directly affect casein kinase 2 activity, but may contribute to its regulation by forming binding sites for interacting proteins and/or targeting it to different compartments (By similarity).DISRUPTION PHENOTYPE Embryonic lethality at 10.5 dpc.MISCELLANEOUS Can use both ATP and GTP as phosphoryl donors. Phosphorylation by casein kinase 2 has been estimated to represent up to one quarter of the eukaryotic phosphoproteome.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CK2 subfamily. UniProt Q60737 1 EQUAL 391 EQUAL Reactome Database ID Release 83 9840136 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=9840136 Reactome R-MMU-201713 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-201713.1 2 Reactome Database ID Release 83 9840138 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=9840138 Reactome R-MMU-5083621 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-5083621.1 CSNK2A2 dimer Reactome DB_ID: 9840143 O54833 CSNK2A2 Reactome DB_ID: 9840141 UniProt:O54833 Csnk2a2 Csnk2a2 FUNCTION Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins.ACTIVITY REGULATION Constitutively active protein kinase whose activity is not directly affected by phosphorylation. Seems to be regulated by level of expression and localization (By similarity).SUBUNIT Heterotetramer composed of two catalytic subunits (alpha chain and/or alpha' chain) and two regulatory subunits (beta chains). The tetramer can exist as a combination of 2 alpha/2 beta, 2 alpha'/2 beta or 1 alpha/1 alpha'/2 beta subunits. Also part of a CK2-SPT16-SSRP1 complex composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B, which forms following UV irradiation. Interacts with RNPS1 (By similarity). Interacts with CSNKA2IP (via C-terminus) (PubMed:19273531). Interacts with SIRT6; preventing CSNK2A2 localization to the nucleus (PubMed:28355567).TISSUE SPECIFICITY Highly expressed in brain, testis and mature epididymal spermatozoa. Weakly expressed in kidney, liver, lung, spleen and thymus (at protein level).DISRUPTION PHENOTYPE Infertile male mice with oligospermia and globozoospermia.MISCELLANEOUS Can use both ATP and GTP as phosphoryl donors. Phosphorylation by casein kinase 2 has been estimated to represent up to one quarter of the eukaryotic phosphoproteome.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CK2 subfamily. UniProt O54833 1 EQUAL 350 EQUAL Reactome Database ID Release 83 9840141 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=9840141 Reactome R-MMU-201721 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-201721.1 2 Reactome Database ID Release 83 9840143 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=9840143 Reactome R-MMU-5083620 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-5083620.1 CSNK2A1:CSNK2A2 Reactome DB_ID: 9840145 1 1 Reactome Database ID Release 83 9840145 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=9840145 Reactome R-MMU-5083623 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-5083623.1 Reactome Database ID Release 83 9840147 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=9840147 Reactome R-MMU-5083624 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-5083624.1 2 CSNK2B P67871 Reactome DB_ID: 9840133 UniProt:P67871 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 9840133 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=9840133 Reactome R-MMU-201693 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-201693.1 2 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 LEFT-TO-RIGHT 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> Prex2 PREX2 Q3LAC4 Reactome DB_ID: 9913172 UniProt:Q3LAC4 Prex2 UniProt Q3LAC4 1 EQUAL 1606 EQUAL Reactome Database ID Release 83 9913172 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=9913172 Reactome R-MMU-8850949 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-8850949.1 Converted from EntitySet in Reactome PTEN, p-3S,2T-PTEN Reactome DB_ID: 9913174 Reactome Database ID Release 83 9913174 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=9913174 Reactome R-MMU-8850937 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-8850937.1 PREX2:PTEN,p-3S,2T-PTEN Reactome DB_ID: 9913176 1 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 LEFT-TO-RIGHT 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> TRIM27 Q62158 Reactome DB_ID: 9913192 UniProt:Q62158 UniProt Q62158 1 EQUAL 513 EQUAL Reactome Database ID Release 83 9913192 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=9913192 Reactome R-MMU-8851002 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-8851002.1 PTEN:TRIM27 Reactome DB_ID: 9913194 1 1 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 LEFT-TO-RIGHT 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> 3 Pten K27polyUb-PTEN O08586 Reactome DB_ID: 9913199 2 EQUAL 403 EQUAL Reactome Database ID Release 83 9913199 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=9913199 Reactome R-MMU-8851009 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-8851009.1 ACTIVATION activeUnit: #Protein163 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). 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). 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