BioPAX pathway converted from "PTEN Regulation" in the Reactome database. PTEN Regulation PTEN Regulation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Regulation of PTEN gene transcription Regulation of PTEN gene transcription This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> SALL4 recruits NuRD to PTEN gene SALL4 recruits NuRD to PTEN gene This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10741462 1 nucleoplasm GO 0005654 NuRD complex [nucleoplasm] NuRD complex Reactome DB_ID: 10734345 1 UniProt:A0A0B4KGZ0 MBD-like Reactome http://www.reactome.org Drosophila melanogaster NCBI Taxonomy 7227 UniProt A0A0B4KGZ0 Chain Coordinates 1 EQUAL 291 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10734343 1 Mi-2 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CHD4 [nucleoplasm] CHD3 [nucleoplasm] CHD3 [nucleoplasm] CHD4 [nucleoplasm] UniProt O97159 UniProt O16102 Converted from EntitySet in Reactome Reactome DB_ID: 10734354 1 (GATAD2A, GATAD2B) [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 10706765 2 UniProt:Q24572 Caf1-55 UniProt Q24572 2 EQUAL 425 EQUAL Reactome DB_ID: 10716450 1 UniProt:A0A0B4KG70 MTA1-like UniProt A0A0B4KG70 1 EQUAL 715 EQUAL Reactome DB_ID: 10704920 1 HDAC1:HDAC2 [nucleoplasm] HDAC1:HDAC2 Reactome DB_ID: 10688492 1 UniProt:Q94517 HDAC1 HDAC1 HDAC1 Rpd3 CG7471 FUNCTION Catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:11571273, PubMed:28245922, PubMed:12408863). Histone deacetylation may constitute a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:11571273, PubMed:8955276, PubMed:15545624, PubMed:15306652). For instance, deacetylation of histone H3 may be a prerequisite for the subsequent recruitment of the histone methyltransferase Su(var)3-9 to histones (PubMed:11571273). Involved in position-effect variegation (PEV) (PubMed:11571273). In the larval brain, part of a regulatory network including the transcriptional repressors klu, dpn and E(spl)mgamma-HLH which is required for type II neuroblast self-renewal and for maintaining erm in an inactive state in intermediate neural progenitors (INP) (PubMed:28245922).SUBUNIT Component of a form of the Esc/E(z) complex present specifically during early embryogenesis which is composed of Caf1-55, esc, E(z), Su(z)12, Pcl and HDAC1 (PubMed:12533794, PubMed:12408863, PubMed:12697833). The Esc/E(z) complex may also associate with Pcl and HDAC1 during early embryogenesis (PubMed:12697833). This complex is distinct from the PRC1 complex, which contains many other PcG proteins like Pc, Ph, Psc, Su(z)2 (PubMed:12533794). The 2 complexes however cooperate and interact together during the first 3 hours of development to establish PcG silencing (PubMed:12533794). Interacts with the histone methyltransferase Su(var)3-9 (PubMed:11571273). Component of a complex that contains at least HDAC1, CoRest and Su(var)3-3/Hdm (PubMed:15306652). Component of the DREAM complex at least composed of Myb, Caf1-55, mip40, mip120, mip130, E2f2, Dp, Rbf, Rbf2, lin-52, HDAC1 and l(3)mbt (PubMed:15545624). Interacts with the chromatin-remodeler Mi-2 (PubMed:18250149).DISRUPTION PHENOTYPE RNAi-mediated knockdown results in loss of type II neuroblasts.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt Q94517 1 EQUAL 482 EQUAL Reactome DB_ID: 10688518 1 1 EQUAL 488 EQUAL Reactome Database ID Release 83 10704920 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10704920 Reactome R-DME-4657004 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-DME-4657004.1 Reactome Database ID Release 83 10741462 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741462 Reactome R-DME-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-DME-4657018.1 Reactome DB_ID: 10741458 1 SALL4:PTEN gene [nucleoplasm] SALL4:PTEN gene Reactome DB_ID: 10741456 1 Ghost homologue of PTEN gene [nucleoplasm] Ghost homologue of PTEN gene Converted from EntitySet in Reactome Reactome DB_ID: 10714693 1 Homologues of SALL4 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity salm [nucleoplasm] salr [nucleoplasm] UniProt P39770 UniProt Q9VKH3 Reactome Database ID Release 83 10741458 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741458 Reactome R-DME-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-DME-8943729.1 Reactome DB_ID: 10741466 1 SALL4:NuRD:PTEN gene [nucleoplasm] SALL4:NuRD:PTEN gene Reactome DB_ID: 10741456 1 Reactome DB_ID: 10741464 1 SALL4:NuRD [nucleoplasm] SALL4:NuRD Reactome DB_ID: 10741462 1 Converted from EntitySet in Reactome Reactome DB_ID: 10714693 1 Reactome Database ID Release 83 10741464 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741464 Reactome R-DME-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-DME-8943778.1 Reactome Database ID Release 83 10741466 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741466 Reactome R-DME-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-DME-8943781.1 Reactome Database ID Release 83 10741468 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741468 Reactome R-DME-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-DME-8943780.1 SALL4 recruits the transcriptional repressor complex NuRD, containing histone deacetylases HDAC1 and HDAC2, to the PTEN gene promoter (Lu et al 2009, Gao et al. 2013). SALL4 may also recruit DNA methyltransferases (DNMTs) to the PTEN promoter (Yang et al. 2012). 23287862 Pubmed 2013 Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex Gao, Chong Dimitrov, Todor Yong, Kol Jia Tatetsu, Hiro Jeong, Ha-Won Luo, Hongbo R Bradner, James E Tenen, Daniel G Chai, Li Blood 121:1413-21 19440552 Pubmed 2009 Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex Lu, J Jeong, HW Kong, N Yang, Y Carroll, J Luo, HR Silberstein, LE Yupoma, LE Chai, L PLoS One 4:e5577 22128185 Pubmed 2012 Stem cell gene SALL4 suppresses transcription through recruitment of DNA methyltransferases Yang, Jianchang Corsello, Tyler R Ma, Yupo J. Biol. Chem. 287:1996-2005 inferred by electronic annotation IEA GO IEA MECOM (EVI1) recruits polycomb repressor complexes (PRCs) to the PTEN gene promoter MECOM (EVI1) recruits polycomb repressor complexes (PRCs) to the PTEN gene promoter This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10741499 1 MECOM:PTEN gene [nucleoplasm] MECOM:PTEN gene Reactome DB_ID: 10741456 1 Converted from EntitySet in Reactome Reactome DB_ID: 10741495 1 Homologues of MECOM [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Dmel\CG10348 [nucleoplasm] ham [nucleoplasm] MECOM [nucleoplasm] Dmel\CG1663 [nucleoplasm] MECOM [nucleoplasm] UniProt Q9VJ55 UniProt Q8I7Z8 UniProt Q8T051 UniProt Q4V6W8 UniProt Q9VEF3 Reactome Database ID Release 83 10741499 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741499 Reactome R-DME-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-DME-8943810.1 Converted from EntitySet in Reactome Reactome DB_ID: 10741497 1 PRC1.4,PRC2 (EZH2) core [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 10741503 1 MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene Reactome DB_ID: 10741456 1 Reactome DB_ID: 10741501 1 MECOM:(PRC1.4,PRC2 (EZH2) core) [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core) Converted from EntitySet in Reactome Reactome DB_ID: 10741495 1 Converted from EntitySet in Reactome Reactome DB_ID: 10741497 1 Reactome Database ID Release 83 10741501 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741501 Reactome R-DME-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-DME-8943820.1 Reactome Database ID Release 83 10741503 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741503 Reactome R-DME-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-DME-8943821.1 Reactome Database ID Release 83 10741505 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741505 Reactome R-DME-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-DME-8943817.1 The transcription factor MECOM (EVI1) can associate with the polycomb repressor complexes (PRCs) and recruit them to the promoter of the PTEN gene (Song et al. 2009). Both the BMI1-containing PRC, supposedly PRC1.4, and the EZH2-containing PRC2 complex are recruited to the PTEN promoter, resulting in transcriptional silencing of the PTEN gene (Song et al. 2009, Yoshimi et al. 2011). Since the exact composition of the EZH2-containing PRC2 at the PTEN promoter is not known, the core EZH2-PRC2 complex is shown. 19884659 Pubmed 2009 The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells Song, Li-Bing Li, J Liao, Wen-Ting Feng, Yan Yu, Chun-Ping Hu, Li-Juan Kong, Qing-Li Xu, Li-Hua Zhang, Xing Liu, Wan-Li Li, Man-Zhi Zhang, L Kang, Tie-Bang Fu, Li-Wu Huang, Wen-Lin Xia, Yun-Fei Tsao, Sai Wah Li, Mengfeng Band, Vimla Band, Hamid Shi, Qing-Hua Zeng, Yi-Xin Zeng, Mu-Sheng J. Clin. Invest. 119:3626-36 21289308 Pubmed 2011 Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins Yoshimi, Akihide Goyama, Susumu Watanabe-Okochi, Naoko Yoshiki, Yumiko Nannya, Yasuhito Nitta, Eriko Arai, Shunya Sato, Tomohiko Shimabe, Munetake Nakagawa, Masahiro Imai, Yoichi Kitamura, Toshio Kurokawa, Mineo Blood 117:3617-28 inferred by electronic annotation IEA GO IEA 2.7.11.1 mTORC1 phosphorylates MAF1 mTORC1 phosphorylates MAF1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10741648 1 cytosol GO 0005829 UniProt:Q7PL26 Maf1 UniProt Q7PL26 1 EQUAL 256 EQUAL Reactome DB_ID: 113592 3 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 10741653 1 O-phospho-L-serine at 60 (in Homo sapiens) 60 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 68 (in Homo sapiens) 68 EQUAL O-phospho-L-serine at 75 (in Homo sapiens) 75 EQUAL 1 EQUAL 256 EQUAL Reactome DB_ID: 29370 3 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10680606 lysosomal membrane GO 0005765 Active mTORC1 complex [lysosomal membrane] Active mTORC1 complex Reactome DB_ID: 10680604 1 mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 [lysosomal membrane] mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Reactome DB_ID: 10680602 1 Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 [lysosomal membrane] Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Reactome DB_ID: 10680600 1 Ragulator:RagA,B:GTP:RagC,D:GDP [lysosomal membrane] Ragulator:RagA,B:GTP:RagC,D:GDP Reactome DB_ID: 10680570 1 Ragulator [lysosomal membrane] Ragulator Reactome DB_ID: 10680553 1 UniProt:Q9V8I2 Lamtor2 UniProt Q9V8I2 1 EQUAL 125 EQUAL Reactome DB_ID: 10680563 1 UniProt:Q9VZL6 Lamtor4 UniProt Q9VZL6 1 EQUAL 99 EQUAL Reactome DB_ID: 10680568 1 UniProt:O96824 Lamtor5 UniProt O96824 1 EQUAL 91 EQUAL Reactome DB_ID: 10680558 1 UniProt:Q9VJD2 Lamtor3 UniProt Q9VJD2 1 EQUAL 124 EQUAL Reactome DB_ID: 10680548 1 UniProt:Q9VW73 Lamtor1 UniProt Q9VW73 2 EQUAL 161 EQUAL Reactome Database ID Release 83 10680570 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10680570 Reactome R-DME-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-DME-5653921.1 Reactome DB_ID: 10680598 1 RagA,B:GTP:RagC,D:GDP [cytosol] RagA,B:GTP:RagC,D:GDP Converted from EntitySet in Reactome Reactome DB_ID: 10680583 1 RRAGA, RRAGB:GTP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 10680596 1 RRAGC,RRAGD:GDP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 83 10680598 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10680598 Reactome R-DME-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-DME-5653945.1 Reactome Database ID Release 83 10680600 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10680600 Reactome R-DME-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-DME-5653979.1 Reactome DB_ID: 10680543 1 Ghost homologue of SLC38A9 [lysosomal membrane] Ghost homologue of SLC38A9 Reactome Database ID Release 83 10680602 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10680602 Reactome R-DME-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-DME-8952725.1 Reactome DB_ID: 10680541 1 mTORC1 [cytosol] mTORC1 Reactome DB_ID: 10680529 1 UniProt:Q9W328 Lst8 UniProt Q9W328 1 EQUAL 326 EQUAL Reactome DB_ID: 10680539 1 UniProt:Q9W437 raptor UniProt Q9W437 1 EQUAL 1335 EQUAL Reactome DB_ID: 10680534 1 UniProt:Q9VK45 Tor UniProt Q9VK45 1 EQUAL 2549 EQUAL Reactome Database ID Release 83 10680541 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10680541 Reactome R-DME-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-DME-377400.1 Reactome Database ID Release 83 10680604 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10680604 Reactome R-DME-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-DME-5653972.1 Reactome DB_ID: 10680522 1 RHEB:GTP [lysosomal membrane] RHEB:GTP Reactome DB_ID: 29438 1 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI 37565 Reactome DB_ID: 10680518 1 UniProt:Q9VND8 Rheb Rheb Rheb CG1081 FUNCTION Binds GTP and exhibits intrinsic GTPase activity (By similarity). Activates the protein kinase activity of TORC1, and thereby plays a role in the regulation of apoptosis (PubMed:22493059). Stimulates the phosphorylation of S6K through activation of TORC1 signaling (PubMed:22493059). May also have a role in activating TORC2 signaling (PubMed:22493059).SIMILARITY Belongs to the small GTPase superfamily. Rheb family. UniProt Q9VND8 1 EQUAL 181 EQUAL Reactome Database ID Release 83 10680522 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10680522 Reactome R-DME-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-DME-165189.1 Reactome Database ID Release 83 10680606 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10680606 Reactome R-DME-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-DME-165678.1 GO 0004674 GO molecular function Reactome Database ID Release 83 10741654 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741654 Reactome Database ID Release 83 10741656 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741656 Reactome R-DME-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-DME-8944454.1 Activated mTORC1 complex phosphorylates the transcription factor MAF1 on serine residues S60, S68 and S75 (Shor et al. 2010, Michels et al. 2010). mTORC1-mediated phosphorylation of MAF1 inhibits translocation of MAF1 to the nucleus (Shor et al. 2010). 20233713 Pubmed 2010 Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells Shor, Boris Wu, Jiang Shakey, Quazi Toral-Barza, Lourdes Shi, Celine Follettie, Max Yu, Ker J. Biol. Chem. 285:15380-92 20516213 Pubmed 2010 mTORC1 directly phosphorylates and regulates human MAF1 Michels, Annemieke A Robitaille, Aaron M Buczynski-Ruchonnet, Diane Hodroj, Wassim Reina, Jaime H Hall, Michael N Hernandez, Nouria Mol. Cell. Biol. 30:3749-57 inferred by electronic annotation IEA GO IEA MAF1 translocates to the nucleus MAF1 translocates to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10741648 1 1 EQUAL 256 EQUAL Reactome DB_ID: 10741646 1 1 EQUAL 256 EQUAL Reactome Database ID Release 83 10741658 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741658 Reactome R-DME-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-DME-8944457.1 Phosphorylation of MAF1 by the activated mTORC1 complex inhibits translocation of MAF1 to the nucleus, and hence its transcriptional activity, but the mechanism has not been elucidated (Shor et al. 2010). inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 83 10741659 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741659 Reactome DB_ID: 10680606 Reactome Database ID Release 83 10751491 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751491 Reactome R-DME-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-DME-8943724.1 Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016). 18172008 Pubmed 2008 Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis Escrivà, Maria Peiró, Sandra Herranz, Nicolás Villagrasa, Patricia Dave, Natàlia Montserrat-Sentís, Bàrbara Murray, Stephen A Francí, Clara Gridley, T Virtanen, Ismo García de Herreros, Antonio Mol. Cell. Biol. 28:1528-40 26910647 Pubmed 2016 MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription Li, Yue Tsang, Chi Kwan Wang, Suihai Li, Xiao-Xing Yang, Yang Fu, Liwu Huang, Wenlin Li, Ming Wang, Hui-Yun Zheng, X F Steven Hepatology 63:1928-42 11781575 Pubmed 2001 The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling Virolle, T Adamson, Eileen D Baron, V Birle, D Mercola, D Mustelin, T de Belle, I Nat. Cell Biol. 3:1124-8 25728608 Pubmed 2015 SLUG is a direct transcriptional repressor of PTEN tumor suppressor Uygur, Berna Abramo, Katrina Leikina, Evgenia Vary, Calvin Liaw, Lucy Wu, Wen-Shu Prostate 75:907-16 17974977 Pubmed 2007 Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras Vasudevan, Krishna Murthi Burikhanov, Ravshan Goswami, Anindya Rangnekar, Vivek M Cancer Res. 67:10343-50 18487508 Pubmed 2008 SALL4 is a key regulator of survival and apoptosis in human leukemic cells Yang, Jianchang Chai, Li Gao, Chong Fowles, Taylor C Alipio, Zaida Dang, Hien Xu, Dan Fink, Louis M Ward, David C Ma, Yupo Blood 112:805-13 16702404 Pubmed 2006 Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1 Zhang, Chun-Li Zou, Yuhua Yu, Ruth T Gage, Fred H Evans, Ronald M Genes Dev. 20:1308-20 16418168 Pubmed 2006 Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells Shen, Ying H Zhang, Lin Gan, Yehua Wang, Xinwen Wang, Jian LeMaire, Scott A Coselli, Joseph S Wang, Xing Li J. Biol. Chem. 281:7727-36 11378386 Pubmed 2001 Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN Patel, L Pass, I Coxon, P Downes, C P Smith, S A MacPhee, C H Curr. Biol. 11:764-8 11545734 Pubmed 2001 Regulation of PTEN transcription by p53 Stambolic, V MacPherson, D Sas, D Lin, Y Snow, B Jang, Y Benchimol, S Mak, T W Mol. Cell 8:317-25 inferred by electronic annotation IEA GO IEA Regulation of PTEN localization Regulation of PTEN localization This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PTEN undergoes monoubiquitination PTEN undergoes monoubiquitination This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10685016 1 UniProt:Q7KMQ6 Pten Pten Dmel_CG5671 CG5671 Pten <submittedName ref="1 2 3 4"> <fullName>Pten, isoform B</fullName> </submittedName> <submittedName> <fullName>IP16020p</fullName> </submittedName> <submittedName> <fullName>Phosphatase PTEN</fullName> </submittedName> UniProt Q7KMQ6 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10671899 1 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity UBI-P63E 2 [cytosol] UBI-P63E 12 [cytosol] UBI-P63E 1 [cytosol] Ubi-p5E [cytosol] UBI-P63E 11 [cytosol] UBI-P63E 3 [cytosol] RpS27A [cytosol] UniProt P0CG69 UniProt P18101 UniProt Q9W418 UniProt P15357 Reactome DB_ID: 10734443 1 ubiquitinylated lysine (Ub [cytosol]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine [MOD:01148] ubiquitinylated lysine (Ub [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10734451 XIAP,NEDD4 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0061630 GO molecular function Reactome Database ID Release 83 10734452 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10734452 Reactome Database ID Release 83 10734454 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10734454 Reactome R-DME-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-DME-6807106.1 When present at low levels in the cell, the E3 ubiquitin ligase XIAP monoubiquitinates PTEN (Van Themsche et al. 2009). NEDD4 (NEDD4-1) can also monoubiquitinate PTEN (Trotman et al. 2007). Monoubiquitination of PTEN on at least lysine residues K13 and K289 causes translocation of PTEN from the cytosol to the nucleus (Trotman et al. 2007, Van Themsche et al. 2009). 19473982 Pubmed 2009 X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization Van Themsche, Céline Leblanc, Valérie Parent, Sophie Asselin, Eric J. Biol. Chem. 284:20462-6 17218261 Pubmed 2007 Ubiquitination regulates PTEN nuclear import and tumor suppression Trotman, Lloyd C Wang, Xinjiang Alimonti, Andrea Chen, Zhenbang Teruya-Feldstein, Julie Yang, Haijuan Pavletich, Nikola P Carver, Brett S Cordon-Cardo, Carlos Erdjument-Bromage, H Tempst, P Chi, Sung-Gil Kim, Hyo-Jong Misteli, Tom Jiang, Xuejun Pandolfi, Pier Paolo Cell 128:141-56 inferred by electronic annotation IEA GO IEA Monoubiquitinated PTEN translocates to the nucleus Monoubiquitinated PTEN translocates to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10734443 1 ubiquitinylated lysine (Ub [cytosol]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine (Ub [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 10734447 1 ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 10734449 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10734449 Reactome R-DME-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-DME-6807105.1 Monoubiquitinated PTEN translocates to the nucleus. Lysine residues K13 and K289 of PTEN are important monoubiquitination targets and their mutation abrogates PTEN nuclear localization (Trotman et al. 2007). inferred by electronic annotation IEA GO IEA 3.4.19.12 USP7 deubiquitinates monoubiquitinated PTEN USP7 deubiquitinates monoubiquitinated PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113518 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 10734447 1 ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 10724993 1 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10671363 2 Ub [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ubi-p5E [nucleoplasm] UBI-P63E 3 [nucleoplasm] UBI-P63E 11 [nucleoplasm] UBI-P63E 1 [nucleoplasm] UBI-P63E 2 [nucleoplasm] RpS27A [nucleoplasm] RpL40 [nucleoplasm] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10715277 UniProt:Q9VYQ8 Usp7 UniProt Q9VYQ8 1 EQUAL 1102 EQUAL GO 0004843 GO molecular function Reactome Database ID Release 83 10715278 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10715278 Reactome Database ID Release 83 10734456 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10734456 Reactome R-DME-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-DME-6807118.1 USP7 (HAUSP) deubiquitinates monoubiquitinated nuclear PTEN, thus promoting relocalization of PTEN to the cytosol. USP7-mediated deubiquitination of PTEN is negatively regulated by PML in the presence of DAXX, but the exact mechanism has not been elucidated (Song et al. 2008). 18716620 Pubmed 2008 The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network Song, MS Salmena, Leonardo Carracedo, Arkaitz Egia, Ainara Lo-Coco, F Teruya-Feldstein, Julie Pandolfi, Pier Paolo Nature 455:813-7 inferred by electronic annotation IEA GO IEA Deubiquitinated PTEN translocates to the cytosol Deubiquitinated PTEN translocates to the cytosol This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10724993 1 2 EQUAL 403 EQUAL Reactome DB_ID: 10685016 1 2 EQUAL 403 EQUAL Reactome Database ID Release 83 10734458 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10734458 Reactome R-DME-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-DME-6807126.1 After nuclear monoubiquitinated PTEN gets deubiquitinated by USP7 (HAUSP), it translocates to the cytosol (Song et al. 2008). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 83 10751367 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751367 Reactome R-DME-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-DME-8948747.1 When monoubiquitinated by E3 ubiquitin ligases XIAP and NEDD4, PTEN translocates from the cytosol to the nucleus (Trotman et al. 2007, Van Themsche et al. 2009). USP7 (HAUSP)-mediated deubiquitination of monoubiquitinated nuclear PTEN promotes relocalization of PTEN to the cytosol (Song et al. 2008). inferred by electronic annotation IEA GO IEA Regulation of PTEN stability and activity Regulation of PTEN stability and activity This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NEDD4, WWP2, CHIP and XIAP polyubiquitinate PTEN NEDD4, WWP2, CHIP and XIAP polyubiquitinate PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10685016 1 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10671899 3 Reactome DB_ID: 10734461 1 ubiquitinylated lysine (polyubiquitin chain [cytosol]) at unknown position 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10734465 NEDD4,STUB1,WWP2 and XIAP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Nedd4 [cytosol] XIAP [cytosol] STUB1 [cytosol] Su(dx) [cytosol] XIAP [cytosol] UniProt Q9VVI3 UniProt Q24307 UniProt Q9XYW6 UniProt Q9Y0H4 UniProt Q24306 Reactome Database ID Release 83 10734466 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10734466 Reactome Database ID Release 83 10734468 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10734468 Reactome R-DME-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-DME-6807134.1 Several ubiquitin ligases, including NEDD4 (Wang et al. 2007), STUB1 (CHIP) (Ahmed et al. 2012), WWP2 (Maddika et al. 2011) and XIAP (Van Themsche et al. 2009) can polyubiquitinate PTEN, targeting it for degradation. 17218260 Pubmed 2007 NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN Wang, Xinjiang Trotman, Lloyd C Koppie, Theresa Alimonti, Andrea Chen, Zhenbang Gao, Zhonghua Wang, Junru Erdjument-Bromage, H Tempst, P Cordon-Cardo, Carlos Pandolfi, Pier Paolo Jiang, Xuejun Cell 128:129-39 21532586 Pubmed 2011 WWP2 is an E3 ubiquitin ligase for PTEN Maddika, Subbareddy Kavela, Sridhar Rani, Neelam Palicharla, Vivek Reddy Pokorny, Jenny L Sarkaria, Jann N Chen, J Nat. Cell Biol. 13:728-33 22427670 Pubmed 2012 The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation Ahmed, Syed Feroj Deb, Satamita Paul, Indranil Chatterjee, Anirban Mandal, Tapashi Chatterjee, Uttara Ghosh, Mrinal K J. Biol. Chem. 287:15996-6006 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT phosphorylates MKRN1 AKT phosphorylates MKRN1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10704168 1 UniProt:Q9VP20 Mkrn1 UniProt Q9VP20 1 EQUAL 482 EQUAL Reactome DB_ID: 113592 1 Reactome DB_ID: 10741818 1 O-phospho-L-serine at 109 (in Homo sapiens) 109 EQUAL 1 EQUAL 482 EQUAL Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10684671 p-T,p-S-AKT [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-T308,S473-AKT1 [cytosol] UniProt Q8INB9 Reactome Database ID Release 83 10684672 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10684672 Reactome Database ID Release 83 10741820 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741820 Reactome R-DME-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-DME-8948757.1 GO 0043491 GO biological process AKT1 (and possibly AKT2 and AKT3), activated in response to EGF treatment, phosphorylates MKRN1, an E3 ubiquitin ligase, on serine residue S109. AKT-mediated phosphorylation results in stabilization of MKRN1, protecting it from ubiquitination and proteasome-mediated degradation (Lee et al. 2015). 26183061 Pubmed 2015 PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis Lee, Min-Sik Jeong, Man-Hyung Lee, Hyun-Woo Han, Hyun-Ji Ko, Aram Hewitt, SM Kim, Jae-Hoon Chun, Kyung-Hee Chung, Joon-Yong Lee, Cheolju Cho, Hanbyoul Song, Jaewhan Nat Commun 6:7769 inferred by electronic annotation IEA GO IEA MKRN1 polyubiquitinates PTEN MKRN1 polyubiquitinates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10685016 1 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10671899 3 Reactome DB_ID: 10734471 1 ubiquitinylated lysine (K48polyUb [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10741818 O-phospho-L-serine at 109 (in Homo sapiens) 109 EQUAL 1 EQUAL 482 EQUAL Reactome Database ID Release 83 10741821 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741821 Reactome Database ID Release 83 10741823 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741823 Reactome R-DME-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-DME-8948775.1 The C-terminal region of the E3 ubiquitin ligase MKRN1 interacts with PTEN and polyubiquitinates it on lysine residue K289, via K48 linkage. AKT-mediated phosphorylation of MKRN1 on serine residue S109 is a pre-requisite for MKRN1 stabilization and MKRN1-mediated ubiquitination of PTEN. MKRN1 is implicated as an oncogene in cervical cancer (Lee et al. 2015). inferred by electronic annotation IEA GO IEA 2.4.2.30 TNKS and TNKS2 PARylate PTEN TNKS and TNKS2 PARylate PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29360 3 NAD(1-) [ChEBI:57540] NAD(1-) NAD(+) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD anion ChEBI 57540 Reactome DB_ID: 10685016 1 2 EQUAL 403 EQUAL Reactome DB_ID: 10741825 1 adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 40 (in Homo sapiens) 40 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 150 (in Homo sapiens) 150 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 326 (in Homo sapiens) 326 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 197277 3 nicotinamide [ChEBI:17154] nicotinamide ChEBI 17154 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10716479 TNKS1/2 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TNKS [cytosol] TNKS2 [cytosol] UniProt Q9VBP3 GO 0003950 GO molecular function Reactome Database ID Release 83 10741826 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741826 Reactome Database ID Release 83 10741828 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741828 Reactome R-DME-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-DME-8948800.1 PTEN can bind tankyrases TNKS (TNKS1) and TNKS2. The interaction involves the tankyrase binding motif at the N-terminus of PTEN (RYQEDG). TNKS and TNKS2 poly-ADP-ribosylate (PARylate) PTEN on glutamic acid residues E40 and E150 and on aspartic acid residue D326. PTEN PARylation is a pre-requisite for RNF146-mediated ubiquitination of PTEN (Li et al. 2015). 25547115 Pubmed 2015 Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth Li, N Zhang, Yajie Han, Xin Liang, Ke Wang, Jiadong Feng, Lin Wang, W Songyang, Z Lin, Chunru Yang, Liuqing Yu, Yonghao Chen, J Genes Dev. 29:157-70 inferred by electronic annotation IEA GO IEA RNF146 polyubiquitinates PARylated PTEN RNF146 polyubiquitinates PARylated PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10741825 1 adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 40 (in Homo sapiens) 40 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 150 (in Homo sapiens) 150 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 326 (in Homo sapiens) 326 EQUAL 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10671899 9 Reactome DB_ID: 10736579 1 adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 40 (in Homo sapiens) 40 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 150 (in Homo sapiens) 150 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 326 (in Homo sapiens) 326 EQUAL ubiquitinylated lysine (polyubiquitin chain [cytosol]) at 342 (in Homo sapiens) 342 EQUAL ubiquitinylated lysine (polyubiquitin chain [cytosol]) at 344 (in Homo sapiens) 344 EQUAL ubiquitinylated lysine (polyubiquitin chain [cytosol]) at 349 (in Homo sapiens) 349 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10716465 UniProt:B7Z078 Rnf146 UniProt B7Z078 1 EQUAL 359 EQUAL Reactome Database ID Release 83 10741829 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741829 Reactome Database ID Release 83 10741831 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10741831 Reactome R-DME-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-DME-8948832.1 The E3 ubiquitin ligase RNF146 possesses a PAR recognition domain (WWE) which binds to PARylated PTEN. RNF146 polyubiquitinates PARylated PTEN, with lysine residues K342, K344 and K349 as major ubiquitination sites. RNF146-mediated ubiquitination targets PTEN for proteasome-mediated degradation (Li et al. 2015). inferred by electronic annotation IEA GO IEA Proteasome degrades polyubiquitinated PTEN Proteasome degrades polyubiquitinated PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10736581 1 PolyUb-PTEN, K48polyUb-K289-PTEN, PolyUb-K324,K344,K349-RibC-E40,E150,D326-PTEN [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Pten [cytosol] phospho-Pten [cytosol] Converted from EntitySet in Reactome Reactome DB_ID: 10671899 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10672015 26S proteasome [cytosol] 26S proteasome Reactome DB_ID: 10671983 1 UniProt:Q9VYG1 UniProt Q9VYG1 2 EQUAL 504 EQUAL Reactome DB_ID: 10671903 1 UniProt:P12881 Prosalpha6 Prosalpha6 Prosalpha6 PROS-35 Pros35 CG4904 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.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel (By similarity). Interacts with PI31.SIMILARITY Belongs to the peptidase T1A family. UniProt P12881 1 EQUAL 263 EQUAL Reactome DB_ID: 10671969 1 Ghost homologue of PSMD10 [cytosol] Ghost homologue of PSMD10 Reactome DB_ID: 10672003 1 UniProt:P22769 Prosalpha4 Prosalpha4 CG3422 PROS-28.1 Prosalpha4 Pros28.1 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.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel (By similarity). Interacts with PI31; this interaction is reduced by PI31 ADP-ribosylation.SIMILARITY Belongs to the peptidase T1A family. UniProt P22769 1 EQUAL 256 EQUAL Reactome DB_ID: 10671971 1 UniProt:Q7KLV9 Rpn6 Rpn6 Rpn6 CG10149 FUNCTION Component of the lid subcomplex of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. In the complex, RPN6 is required for proteasome assembly (By similarity). May act as linker between 19S regulatory subunit and the 20S proteasome core.SUBUNIT Component of the lid subcomplex of the 19S proteasome regulatory particle complex (also named PA700 complex). The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. Interacts with alien/CSN2. Interacts with Prosalpha2 and Rpt6.DEVELOPMENTAL STAGE Highly expressed in the female germline, more precisely in the nurse cells of maturing egg chambers. Also detected in the somatic follicle cells. Highly expressed during oogenesis and early blastoderm embryos. After the beginning of zygotic transcription, present in the elongating germband and later in the mesodermal region and the developing hindgut and posterior midgut. In late embryos, shortly before hatching, becomes restricted to the brain hemispheres, the central nervous system, the embryonic gonads and the gut. In third instar larval tissues, expressed in the larval brain and in all imaginal disks.DISRUPTION PHENOTYPE Embryos develop and hatch normally but fail to outlive early larval stages. During the first and second instar larval stages larvae become immobile and sluggish and die without any observable defects. Lethality is probably the result of additive defects in overall cell proliferation rather than of distinct developmental disorders.SIMILARITY Belongs to the proteasome subunit S9 family. UniProt Q7KLV9 2 EQUAL 422 EQUAL Reactome DB_ID: 10671955 1 UniProt:P48601 Rpt2 Rpt2 CG5289 Rpt2 Pros26.4 P26s4 FUNCTION The 26S proteasome is involved in the ATP-dependent degradation of ubiquitinated proteins. The regulatory (or ATPase) complex confers ATP dependency and substrate specificity to the 26S complex (By similarity).SUBUNIT Interacts with PSMD5.SIMILARITY Belongs to the AAA ATPase family. UniProt P48601 2 EQUAL 440 EQUAL Reactome DB_ID: 10671965 1 UniProt:Q9W414 Rpt4 UniProt Q9W414 1 EQUAL 389 EQUAL Reactome DB_ID: 10671935 1 UniProt:Q9XYN7 Prosbeta3 Prosbeta3 Prosbeta3 CG11981 FUNCTION Non-catalytic component of the proteasome, 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.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel (By similarity).SIMILARITY Belongs to the peptidase T1B family. UniProt Q9XYN7 2 EQUAL 205 EQUAL Reactome DB_ID: 10671993 1 UniProt:Q9V3P3 REG UniProt Q9V3P3 1 EQUAL 249 EQUAL Reactome DB_ID: 10672001 1 Ghost homologue of PSME4 [cytosol] Ghost homologue of PSME4 Reactome DB_ID: 10671943 1 UniProt:Q9VUJ1 Prosbeta2 Prosbeta2 Prosbeta2 Dmel_CG3329 Pros-beta-2 CG3329 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 (By similarity).CATALYTIC ACTIVITY Cleavage of peptide bonds with very broad specificity.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 (By similarity).SIMILARITY Belongs to the peptidase T1B family. UniProt Q9VUJ1 44 EQUAL 277 EQUAL Reactome DB_ID: 10671933 1 UniProt:Q9VJJ0 CG17331 CG17331 CG17331 Dmel_CG17331 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 (By similarity).CATALYTIC ACTIVITY Cleavage of peptide bonds with very broad specificity.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 (By similarity).SIMILARITY Belongs to the peptidase T1B family. UniProt Q9VJJ0 1 EQUAL 201 EQUAL Reactome DB_ID: 10671973 1 UniProt:Q9V3Z4 Rpn5 Rpn5 CG1100 Rpn5 Dmel_CG1100 SIMILARITY Contains 1 PCI domain. UniProt Q9V3Z4 2 EQUAL 456 EQUAL Reactome DB_ID: 10671989 1 UniProt:Q9V436 Rpn12 Rpn12 CG4157 Rpn12 Dmel_CG4157 <submittedName> <fullName>Rpn12</fullName> </submittedName> <submittedName> <fullName>26S proteasome regulatory complex subunit p30</fullName> </submittedName> <submittedName> <fullName>RE36854p</fullName> </submittedName> UniProt Q9V436 1 EQUAL 350 EQUAL Reactome DB_ID: 10671937 1 UniProt:Q9VNA5 Prosbeta7 Prosbeta7 Prosbeta4 Prosb4 CG12000 Prosbeta7 FUNCTION Non-catalytic component of the proteasome, 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 (By similarity).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel (By similarity).SIMILARITY Belongs to the peptidase T1B family. UniProt Q9VNA5 46 EQUAL 264 EQUAL Reactome DB_ID: 10671957 1 UniProt:Q7KMQ0 Rpt1 Rpt1 Dmel_CG1341 CG1341 Rpt1 SIMILARITY Belongs to the AAA ATPase family. UniProt Q7KMQ0 2 EQUAL 433 EQUAL Reactome DB_ID: 10671975 1 UniProt:Q7KMP8 Rpn9 Rpn9 Dmel_CG10230 CG10230 Rpn9 <submittedName> <fullName>Rpn9, isoform A</fullName> </submittedName> <submittedName> <fullName>26S proteasome regulatory complex subunit p39A</fullName> </submittedName> <submittedName> <fullName>LD17530p</fullName> </submittedName> UniProt Q7KMP8 1 EQUAL 376 EQUAL Reactome DB_ID: 10671913 1 UniProt:Q9XZJ4 Prosalpha1 Prosalpha1 Prosalpha1 CG18495 Prosalpha6 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 (By similarity).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel (By similarity). Interacts with PI31.SIMILARITY Belongs to the peptidase T1A family. UniProt Q9XZJ4 1 EQUAL 246 EQUAL Reactome DB_ID: 10671901 1 UniProt:Q9V3H2 Rpn11 Rpn11 CG18174 Rpn11 yip5 FUNCTION Metalloprotease component of the 26S proteasome that specifically cleaves 'Lys-63'-linked polyubiquitin chains. The 26S proteasome is involved in the ATP-dependent degradation of ubiquitinated proteins. The function of the 'Lys-63'-specific deubiquitination of the proteasome is unclear (By similarity).SUBUNIT Component of the 19S regulatory cap of the 26S proteasome.SIMILARITY Belongs to the peptidase M67A family. PSMD14 subfamily. UniProt Q9V3H2 1 EQUAL 310 EQUAL Reactome DB_ID: 10671953 1 UniProt:A0AQH0 Prosbeta1 UniProt A0AQH0 21 EQUAL 219 EQUAL Reactome DB_ID: 10671987 1 UniProt:P26270 Rpn8 Rpn8 Mov34 Rpn8 CG3416 FUNCTION Acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins.SIMILARITY Belongs to the peptidase M67A family. UniProt P26270 1 EQUAL 324 EQUAL Reactome DB_ID: 10671939 1 UniProt:Q7K148 Prosbeta5 UniProt Q7K148 60 EQUAL 263 EQUAL Reactome DB_ID: 10671909 1 UniProt:P18053 Prosalpha3 UniProt P18053 1 EQUAL 261 EQUAL Reactome DB_ID: 10671961 1 UniProt:Q9V405 Rpt3 Rpt3 CG16916 Rpt3-RA Rpt3 Dmel_CG16916 SIMILARITY Belongs to the AAA ATPase family. UniProt Q9V405 1 EQUAL 418 EQUAL Reactome DB_ID: 10671977 1 UniProt:Q9VW54 Rpn1 Rpn1 Dmel_CG7762 Rpn1 CG7762 <submittedName> <fullName>Rpn1</fullName> </submittedName> <submittedName> <fullName>26S proteasome regulatory complex subunit p97</fullName> </submittedName> <submittedName> <fullName>Putative uncharacterized protein</fullName> </submittedName> UniProt Q9VW54 1 EQUAL 908 EQUAL Reactome DB_ID: 10671967 1 UniProt:Q9V3P6 Rpn2 Rpn2 Rpn2 CG11888 FUNCTION Acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins.SIMILARITY Belongs to the proteasome subunit S1 family. UniProt Q9V3P6 1 EQUAL 953 EQUAL Reactome DB_ID: 10671907 1 UniProt:Q9V5C6 Prosalpha7 Prosalpha7 CG1519 Prosalpha7 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 (By similarity).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel (By similarity). Interacts with ntc.SIMILARITY Belongs to the peptidase T1A family. UniProt Q9V5C6 2 EQUAL 255 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10671951 1 Homologues of PSMB8 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Prosbeta5 [cytosol] Prosbeta5R2 [cytosol] Prosbeta5R1 [cytosol] UniProt Q8INY4 UniProt Q9W1S5 Reactome DB_ID: 10671981 1 UniProt:P55035 Rpn10 Rpn10 Rpn10 PROS-54 Pros54 CG7619 FUNCTION Binds and presumably selects ubiquitin-conjugates for destruction.SUBUNIT The 26S proteasome is composed of a core protease, known as the 20S proteasome, capped at one or both ends by the 19S regulatory complex (RC). The RC is composed of at least 18 different subunits in two subcomplexes, the base and the lid, which form the portions proximal and distal to the 20S proteolytic core, respectively (By similarity). Interacts with Ubc4.SIMILARITY Belongs to the proteasome subunit S5A family. UniProt P55035 1 EQUAL 377 EQUAL Reactome DB_ID: 10671911 1 UniProt:Q95083 Prosalpha5 Prosalpha5 Prosalpha5 ProsMA5 CG10938 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.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel (By similarity).SIMILARITY Belongs to the peptidase T1A family. UniProt Q95083 1 EQUAL 241 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10671931 1 Homologues of PSMB10 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Prosbeta2R1 [cytosol] Prosbeta2 [cytosol] Prosbeta2R2 [cytosol] UniProt Q9W470 UniProt Q8T915 Reactome DB_ID: 10672013 1 Ghost homologue of SEM1 [cytosol] Ghost homologue of SEM1 Reactome DB_ID: 10671923 1 Ghost homologue of PSMB1 [cytosol] Ghost homologue of PSMB1 Reactome DB_ID: 10671995 1 2 EQUAL 239 EQUAL Reactome DB_ID: 10671999 1 UniProt:Q9V637 PI31 UniProt Q9V637 1 EQUAL 271 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10672011 1 Homologues of PSMB11 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Prosbeta5 [cytosol] Prosbeta5R2 [cytosol] Prosbeta5R1 [cytosol] Reactome DB_ID: 10671959 1 UniProt:Q9V3V6 Tbp-1 Tbp-1 Dmel_CG10370 Tbp-1 CG10370 SIMILARITY Belongs to the AAA ATPase family. UniProt Q9V3V6 1 EQUAL 439 EQUAL Reactome DB_ID: 10671979 1 UniProt:P25161 Rpn3 Rpn3 Rpn3 CG42641 Dox-A2 FUNCTION Acts as a regulatory subunit of the 26 proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins.SUBUNIT The 26S proteasome is composed of a core protease, known as the 20S proteasome, capped at one or both ends by the 19S regulatory complex (RC). The RC is composed of at least 18 different subunits in two subcomplexes, the base and the lid, which form the portions proximal and distal to the 20S proteolytic core, respectively (By similarity).TISSUE SPECIFICITY Blood (crystal) cells and cuticle.SIMILARITY Belongs to the proteasome subunit S3 family.CAUTION Was originally thought to be the diphenol oxidase A2 component involved in catecholamine metabolism, melanin formation, and sclerotization of the cuticle. UniProt P25161 1 EQUAL 534 EQUAL Reactome DB_ID: 10671905 1 UniProt:P40301 Prosalpha2 Prosalpha2 Prosalpha2 PROS-25 Pros25 CG5266 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.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel (By similarity). Interacts with Rpn6.SIMILARITY Belongs to the peptidase T1A family. UniProt P40301 2 EQUAL 234 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10671921 1 Homologues of PSMA7 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Prosalpha4T1 [cytosol] Prosalpha4 [cytosol] Prosalpha4T2 [cytosol] UniProt Q24178 UniProt Q27575 Reactome DB_ID: 10671963 1 UniProt:O18413 Rpt6 Rpt6 Ug Rpt6 DUG Pros45 CG1489 FUNCTION The 26S proteasome is involved in the ATP-dependent degradation of ubiquitinated proteins. The regulatory (or ATPase) complex confers ATP dependency and substrate specificity to the 26S complex (By similarity).SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. Interacts with Rpn6 (PubMed:22187461). Interacts with imd and Usp2 isoform A (PubMed:25027767).SIMILARITY Belongs to the AAA ATPase family. UniProt O18413 2 EQUAL 406 EQUAL Reactome DB_ID: 10671941 1 35 EQUAL 239 EQUAL Reactome DB_ID: 10671985 1 UniProt:Q9V3G7 Rpn7 Rpn7 Rpn7 CG5378 FUNCTION Acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins.SIMILARITY Belongs to the proteasome subunit S10 family. UniProt Q9V3G7 1 EQUAL 389 EQUAL Reactome DB_ID: 10671991 1 UniProt:Q9VFS8 UniProt Q9VFS8 1 EQUAL 223 EQUAL Reactome DB_ID: 10671997 1 2 EQUAL 254 EQUAL Reactome Database ID Release 83 10672015 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10672015 Reactome R-DME-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-DME-68819.1 GO 0004175 GO molecular function Reactome Database ID Release 83 10672016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10672016 Reactome Database ID Release 83 10736583 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10736583 Reactome R-DME-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-DME-8850992.1 PTEN, polyubiquitinated by either NEDD4 (Wang et al. 2007), STUB1 (CHIP) (Ahmed et al. 2011), WWP2 (Maddika et al. 2011), XIAP (Van Themsche et al. 2009), MKRN1 (Lee et al. 2015) or RNF146 (Li et al. 2015), is degraded by the proteasome. inferred by electronic annotation IEA GO IEA 3.4.19.12 USP13 and OTUD3 deubiquitinate PTEN USP13 and OTUD3 deubiquitinate PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10734471 1 ubiquitinylated lysine (K48polyUb [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 29356 1 Reactome DB_ID: 10685016 1 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10671899 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10734478 USP13,OTUD3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity otu [cytosol] USP13 [cytosol] UniProt P10383 UniProt Q9VZU7 Reactome Database ID Release 83 10734479 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10734479 Reactome Database ID Release 83 10734481 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10734481 Reactome R-DME-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-DME-6807206.1 Several ubiquitin proteases deubiquitinate polyubiquitinated PTEN. USP13 and OTUD3 prolong the half-life of PTEN by preventing its proteasome-mediated degradation. Loss of USP13 or OTUD3 expression promotes AKT activation and cancer aggressiveness (Zhang et al. 2013, Yuan et al. 2015). 24270891 Pubmed 2013 Deubiquitylation and stabilization of PTEN by USP13 Zhang, Jinsong Zhang, Peijing Wei, Yongkun Piao, Hai-Long Wang, W Maddika, Subbareddy Wang, Min Chen, Dahu Sun, Yutong Hung, Mien-Chie Chen, J Ma, Li Nat. Cell Biol. 15:1486-94 26280536 Pubmed 2015 Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis Yuan, Lin Lv, Yanrong Li, Hongchang Gao, Haidong Song, Shanshan Zhang, Yuan Xing, Guichun Kong, Xiangzhen Wang, Lijing Li, Yang Zhou, Tao Gao, Daming Xiao, Zhi-Xiong Yin, Yuxin Wei, Wenyi He, Fuchu Zhang, Lingqiang Nat. Cell Biol. 17:1169-81 inferred by electronic annotation IEA GO IEA PTEN binds FRK PTEN binds FRK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10736016 1 UniProt:Q9V9J3 Src42A Src42A Src41 Src42A CG44128 TK5 FUNCTION Required directly or indirectly for the phosphorylation of drpr which is necessary for the interaction of drpr with shark and subsequent glial phagocytic activity (PubMed:18432193). Together with drpr and shark, promotes the migration of macrophages to sites of wounding as part of a signaling cascade where Scr42a detects production of hydrogen peroxide at wound sites which triggers phosphorylation of drpr and subsequent recruitment and activation of shark (PubMed:26028435). Essential for correct eye morphogenesis (ommatidial R7 neuron formation) which requires the Ras1/MAPK signal transduction pathway (PubMed:8682295). May be involved in the regulation of cytoskeleton organization and cell-cell contacts in developing ommatidia (PubMed:8682295). During embryogenesis, involved in regulation of dorsal closure where it may have a role in activating the JNK pathway in leading edge cells during this process (PubMed:16831834).TISSUE SPECIFICITY Ubiquitous in early embryos, in stages 13-16 expression is seen in visceral mesoderm, hindgut, brain, anal pads and ventral ganglions. In larvae, expression is in CNS, wing disk, leg disk and photoreceptor precursors in the eye-antenna disks posterior to the morphogenetic furrow.DEVELOPMENTAL STAGE In early embryos expression is very low, expression increases during embryogenesis. Also expressed in larvae and pupae.DISRUPTION PHENOTYPE Following epithelial wounding, no migration of macrophages to wound sites (PubMed:26028435). RNAi-mediated knockdown in glial cells potently suppresses glial phagocytic activity with drpr not recruited to severed maxillary palp axons, blockage of glial hypertrophy, blockage of drpr up-regulation after antennal ablation and reduced clearance of severed axons in the central nervous system (PubMed:18432193).SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. UniProt Q9V9J3 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL O4'-phospho-L-tyrosine [MOD:00048] 1 EQUAL 505 EQUAL Reactome DB_ID: 10685016 1 2 EQUAL 403 EQUAL Reactome DB_ID: 10736018 1 PTEN:p-Y387-FRK [cytosol] PTEN:p-Y387-FRK Reactome DB_ID: 10736016 1 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL 1 EQUAL 505 EQUAL Reactome DB_ID: 10685016 1 2 EQUAL 403 EQUAL Reactome Database ID Release 83 10736018 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10736018 Reactome R-DME-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-DME-8847960.1 Reactome Database ID Release 83 10736020 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10736020 Reactome R-DME-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-DME-8847968.1 FRK (RAK), a SRC family member kinase, binds PTEN. The interaction involves the SH3 domain of FRK and the C2 domain of PTEN (Yim et al. 2009). Like other SRC family members, FRK is autophosphorylated on a C-terminal tyrosine residue Y387. FRK possesses a nuclear localization signal and is found in both nucleus and the cytosol (Cance et al. 1994). 19345329 Pubmed 2009 Rak functions as a tumor suppressor by regulating PTEN protein stability and function Yim, Eun-Kyoung Peng, Guang Dai, Hui Hu, Ruozhen Li, Kaiyi Lu, Yiling Mills, Gordon B Meric-Bernstam, Funda Hennessy, Bryan T Craven, Rolf J Lin, Shiaw-Yih Cancer Cell 15:304-14 7696183 Pubmed 1994 Rak, a novel nuclear tyrosine kinase expressed in epithelial cells Cance, W G Craven, R J Bergman, M Xu, L Alitalo, K Liu, E T Cell Growth Differ. 5:1347-55 inferred by electronic annotation IEA GO IEA 2.7.10.2 FRK phosphorylates PTEN FRK phosphorylates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10736018 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 10736016 1 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL 1 EQUAL 505 EQUAL Reactome DB_ID: 29370 1 Reactome DB_ID: 10736023 1 O4'-phospho-L-tyrosine at 336 (in Homo sapiens) 336 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10736018 GO 0004713 GO molecular function Reactome Database ID Release 83 10736024 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10736024 Reactome Database ID Release 83 10736026 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10736026 Reactome R-DME-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-DME-8847977.1 FRK tyrosine kinase (RAK) phosphorylates PTEN on tyrosine residue Y336. FRK-mediated phosphorylation inhibits NEDD4-mediated polyubiquitination and subsequent degradation of PTEN, thus increasing PTEN half-life. FRK-mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). inferred by electronic annotation IEA GO IEA 2.7.11.1 Casein kinase II phosphorylates PTEN Casein kinase II phosphorylates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10685016 1 2 EQUAL 403 EQUAL Reactome DB_ID: 113592 5 Reactome DB_ID: 10736569 1 O-phospho-L-serine at 370 (in Homo sapiens) 370 EQUAL O-phospho-L-serine at 380 (in Homo sapiens) 380 EQUAL O-phospho-L-threonine at 382 (in Homo sapiens) 382 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-threonine at 383 (in Homo sapiens) 383 EQUAL O-phospho-L-serine at 385 (in Homo sapiens) 385 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 29370 5 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10685706 Casein kinase II [cytosol] Casein kinase II Converted from EntitySet in Reactome Reactome DB_ID: 10685704 2 CSNK2(A1:A1/A1:A2/A2:A2) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 10685690 2 UniProt:P08182 CkIIbeta CkIIbeta CkIIbeta Cask-II-b CG15224 FUNCTION Participates in Wnt signaling (By similarity). Plays a complex role in regulating the basal catalytic activity of the alpha subunit.SUBUNIT Tetramer of two alpha and two beta subunits.PTM Phosphorylated by alpha subunit.SIMILARITY Belongs to the casein kinase 2 subunit beta family. UniProt P08182 2 EQUAL 215 EQUAL Reactome Database ID Release 83 10685706 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10685706 Reactome R-DME-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-DME-201711.1 Reactome Database ID Release 83 10685707 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10685707 Reactome Database ID Release 83 10736571 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10736571 Reactome R-DME-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-DME-8850945.1 Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. S370 and S385 are the main CK2 phosphorylation sites in PTEN (Torres and Pulido 2001, Miller et al. 2002). CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002). 11035045 Pubmed 2001 The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation Torres, J Pulido, R J. Biol. Chem. 276:993-8 12297295 Pubmed 2002 Direct identification of PTEN phosphorylation sites Miller, Susan J Lou, David Y Seldin, David C Lane, William S Neel, Benjamin G FEBS Lett. 528:145-53 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 83 10751371 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751371 Reactome R-DME-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-DME-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). 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 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 83 10751369 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751369 Reactome R-DME-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-DME-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 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 20080666 Pubmed 2010 Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship Kim, Hyunsoo Huang, Wei Jiang, Xiuli Pennicooke, Brenton Park, Peter J Johnson, Mark D Proc. Natl. Acad. Sci. U.S.A. 107:2183-8 25737250 Pubmed 2015 Differential thiol oxidation of the signaling proteins Akt, PTEN or PP2A determines whether Akt phosphorylation is enhanced or inhibited by oxidative stress in C2C12 myotubes derived from skeletal muscle Tan, Pearl Lin Shavlakadze, Tea Grounds, Miranda D Arthur, Peter G Int. J. Biochem. Cell Biol. 62:72-9 26415504 Pubmed 2015 AIF inhibits tumor metastasis by protecting PTEN from oxidation Shen, Shao-Ming Guo, Meng Xiong, Zhong Yu, Yun Zhao, Xu-Yun Zhang, Fei-Fei Chen, Guo-Qiang EMBO Rep. 16:1563-80 18327259 Pubmed 2008 Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes Xiao, Changchun Srinivasan, Lakshmi Calado, Dinis Pedro Patterson, Heide Christine Zhang, Baochun Wang, Jing Henderson, Joel M Kutok, Jeffrey L Rajewsky, Klaus Nat. Immunol. 9:405-14 23013792 Pubmed 2012 Regulation of the tumor suppressor PTEN by SUMO González-Santamaría, J Campagna, M Ortega-Molina, A Marcos-Villar, L de la Cruz-Herrera, C F González, D Gallego, P Lopitz-Otsoa, F Esteban, M Rodriguez, M S Serrano, M Rivas, C Cell Death Dis 3:e393 25884169 Pubmed 2015 Lung neuroendocrine tumors: correlation of ubiquitinylation and sumoylation with nucleo-cytosolic partitioning of PTEN Collaud, Stéphane Tischler, Verena Atanassoff, Andrej Wiedl, Thomas Komminoth, Paul Oehlschlegel, Christian Weder, Walter Soltermann, A BMC Cancer 15:74 24429633 Pubmed 2014 The multilayered complexity of ceRNA crosstalk and competition Tay, Yvonne Rinn, John Pandolfi, Pier Paolo Nature 505:344-52 inferred by electronic annotation IEA GO IEA