BioPAX pathway converted from "PIP3 activates AKT signaling" in the Reactome database. PIP3 activates AKT signaling PIP3 activates AKT signaling PI3K/AKT Signaling 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> RAC1,RAC2,RHOG activate PI3K RAC1,RAC2,RHOG activate PI3K 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: 10257614 1 cytosol GO 0005829 PI3K alpha [cytosol] PI3K alpha Reactome DB_ID: 10254418 1 UniProt:A0A5K1UB41 PIK3CA Reactome http://www.reactome.org Sus scrofa NCBI Taxonomy 9823 UniProt A0A5K1UB41 Chain Coordinates 1 EQUAL 1068 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10257612 1 PI3K-regulatory subunits [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PIK3R1 [cytosol] UniProt I3LLB7 Reactome Database ID Release 82 10257614 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10257614 Reactome R-SSC-198379 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-198379.1 Converted from EntitySet in Reactome Reactome DB_ID: 10257606 1 plasma membrane GO 0005886 RAC1:GTP,RAC2:GTP,RHOG:GTP [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 10257616 1 RAC1:GTP,RAC2:GTP,RHOG:GTP:PI3K alpha [plasma membrane] RAC1:GTP,RAC2:GTP,RHOG:GTP:PI3K alpha Reactome DB_ID: 10257614 1 Converted from EntitySet in Reactome Reactome DB_ID: 10257606 1 Reactome Database ID Release 82 10257616 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10257616 Reactome R-SSC-114540 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-114540.1 Reactome Database ID Release 82 10257618 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10257618 Reactome R-SSC-114542 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-114542.1 PIP3 produced by PI3K activity is essential for receptor-driven stimulation of Rac activation, but PI3K also lies downstream of Rac, as Rac1 can form a complex with PI3K alpha leading to its activation. 8645157 Pubmed 1996 Rac GTPase interacts specifically with phosphatidylinositol 3-kinase Bokoch, GM Vlahos, CJ Wang, Y Knaus, UG Traynor-Kaplan, AE Biochem J 315:775-9 7744773 Pubmed 1995 Phosphoinositide 3-kinase inhibition spares actin assembly in activating platelets but reverses platelet aggregation Kovacsovics, TJ Bachelot, C Toker, A Vlahos, CJ Duckworth, B Cantley, Lewis C Hartwig, JH J Biol Chem 270:11358-66 11803464 Pubmed 2002 Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-kappaB Murga, C Zohar, M Teramoto, H Gutkind, JS Oncogene 21:207-16 7627555 Pubmed 1995 PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase Hawkins, PT Eguinoa, A Qiu, RG Stokoe, D Cooke, FT Walters, R Wennström, S Claesson-Welsh, Lena Evans, T Symons, M Curr Biol 5:393-403 inferred by electronic annotation IEA GO IEA 2.7.1.153 PI3K phosphorylates PIP2 to PIP3 PI3K phosphorylates PIP2 to PIP3 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: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 179856 1 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) [ChEBI:58456] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) 2,3-bis(alkanoyloxy)propyl (1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-bis(phosphonatooxy)cyclohexyl phosphate a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) ChEBI 58456 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 179838 1 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) [ChEBI:57836] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) 2,3-bis(alkanoyloxy)propyl (1S,2S,3R,4S,5S,6S)-2,6-dihydroxy-3,4,5-tris(phosphonatooxy)cyclohexyl phosphate ChEBI 57836 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10304743 Activator:PI3K [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0046934 GO molecular function Reactome Database ID Release 82 10304744 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10304744 Reactome Database ID Release 82 10304750 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10304750 Reactome R-SSC-2316434 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2316434.1 GO 0051897 GO biological process A number of different extracellular signals converge on PI3K activation. PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as FGFR (Ong et al. 2001, Eswarakumar et al. 2005), KIT (Chian et al. 2001, Ronnstrand 2004, Reber et al. 2006), PDGF (Coughlin et al. 1989, Fantl et al. 1992, Heldin et al. 1998), insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995), and EGFR and its family members (Rodrigues et al. 2000, Jackson et al. 2004, Kainulainen et al. 2000, Junttila et al. 2009). Other proteins, such as CD28 (Pages et al. 1996, Koyasu 2003, Kane and Weiss, 2003) and TRAT1 (Bruyns et al. 1998, Koyasu 2003, Kolsch et al. 2006), can also trigger PI3K activity.<br><br>In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011). 16612002 Pubmed 2006 Normal T-cell development and immune functions in TRIM-deficient mice Kolsch, U Arndt, B Reinhold, D Lindquist, JA Juling, N Kliche, S Pfeffer, K Bruyns, E Schraven, B Simeoni, L Mol Cell Biol 26:3639-48 10722704 Pubmed 2000 A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis Kainulainen, V Sundvall, M Määttä, JA Santiestevan, E Klagsbrun, Michael Elenius, K J Biol Chem 275:8641-9 21827948 Pubmed 2011 Dynamics of the phosphoinositide 3-kinase p110? interaction with p85? and membranes reveals aspects of regulation distinct from p110? Burke, John E Vadas, Oscar Berndt, Alex Finegan, Tara Perisic, O Williams, RL Structure 19:1127-37 11353842 Pubmed 2001 Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins Ong, SH Hadari, YR Gotoh, N Guy, GR Schlessinger, J Lax, I Proc Natl Acad Sci U S A 98:6074-9 2466336 Pubmed 1989 Role of phosphatidylinositol kinase in PDGF receptor signal transduction Coughlin, SR Escobedo, JA Williams, LT Science 243:1191-4 16483568 Pubmed 2006 Stem cell factor and its receptor c-Kit as targets for inflammatory diseases Reber, L Da Silva, CA Frossard, N Eur J Pharmacol 533:327-40 10648629 Pubmed 2000 A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling Rodrigues, GA Falasca, M Zhang, Z Ong, SH Schlessinger, J Mol Cell Biol 20:1448-59 15526160 Pubmed 2004 Signal transduction via the stem cell factor receptor/c-Kit Rönnstrand, Lars Cell Mol Life Sci 61:2535-48 15059917 Pubmed 2004 Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects Jackson, JG St Clair, P Sliwkowski, MX Brattain, Michael G Cancer Res 64:2601-9 12660731 Pubmed 2003 The role of PI3K in immune cells Koyasu, S Nat Immunol 4:313-9 15863030 Pubmed 2005 Cellular signaling by fibroblast growth factor receptors Eswarakumar, VP Lax, I Schlessinger, J Cytokine Growth Factor Rev 16:139-49 8621607 Pubmed 1996 Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association Pagès, F Ragueneau, M Klasen, S Battifora, M Couez, D Sweet, R Truneh, A Ward, SG Olive, D J Biol Chem 271:9403-9 19411071 Pubmed 2009 Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941 Junttila, TT Akita, Robert W Parsons, K Fields, C Lewis Phillips, GD Friedman, LS Sampath, D Sliwkowski, MX Cancer Cell 15:429-40 1381348 Pubmed 1992 Insulin and insulinomimetic agents induce activation of phosphatidylinositol 3'-kinase upon its association with pp185 (IRS-1) in intact rat livers Hadari, Yaron Tzahar, E Nadiv, Orna Rothenberg, Paul Roberts, Charles LeRoith, Derek Yarden, Y Zick, Yehiel J. Biol. Chem. 267:17483-6 11520784 Pubmed 2001 Phosphatidylinositol 3 kinase contributes to the transformation of hematopoietic cells by the D816V c-Kit mutant Chian, R Young, S Danilkovitch-Miagkova, A Rönnstrand, Lars Leonard, E Ferrao, P Ashman, L Linnekin, D Blood 98:1365-73 9687533 Pubmed 1998 T cell receptor (TCR) interacting molecule (TRIM), a novel disulfide-linked dimer associated with the TCR-CD3-zeta complex, recruits intracellular signaling proteins to the plasma membrane Bruyns, E Marie-Cardine, A Kirchgessner, H Sagolla, K Shevchenko, A Mann, M Autschbach, F Bensussan, A Meuer, S Schraven, B J Exp Med 188:561-75 9739761 Pubmed 1998 Signal transduction via platelet-derived growth factor receptors Heldin, Carl-Henrik Ostman, A Rönnstrand, Lars Biochim Biophys Acta 1378:F79-113 19805105 Pubmed 2009 A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane Mandelker, Diana Gabelli, Sandra B Schmidt-Kittler, Oleg Zhu, Jiuxiang Cheong, Ian Huang, Chuan-Hsiang Kinzler, KW Vogelstein, B Amzel, L Mario Proc. Natl. Acad. Sci. U.S.A. 106:16996-7001 7543144 Pubmed 1995 Insulin-like growth factor induces phosphorylation of immunoreactive insulin receptor substrate and its association with phosphatidylinositol-3 kinase in human thymocytes Kooijman, Ron Lauf, Jeroen Kappers, Astrid Rijkers, Ger J. Exp. Med. 182:593-7 1374684 Pubmed 1992 Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways Fantl, WJ Escobedo, JA Martin, GA Turck, CW del Rosario, M McCormick, F Williams, LT Cell 69:413-23 12670391 Pubmed 2003 The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3 Kane, LP Weiss, A Immunol Rev 192:7-20 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 82 10304751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10304751 Reactome DB_ID: 10304748 IL33:IL1RL1:IL1RAP-1:MYD88 dimer:IRAK1,IRAK4,TRAF6 [plasma membrane] IL33:IL1RL1:IL1RAP-1:MYD88 dimer:IRAK1,IRAK4,TRAF6 Reactome DB_ID: 10261432 1 UniProt:A7XUJ6 TRAF6 UniProt A7XUJ6 1 EQUAL 522 EQUAL Reactome DB_ID: 10304746 1 IL33:IL1RL1:IL1RAP-1:MYD88 dimer [plasma membrane] IL33:IL1RL1:IL1RAP-1:MYD88 dimer Reactome DB_ID: 10265503 1 MYD88 dimer [cytosol] MYD88 dimer Reactome DB_ID: 10265501 2 UniProt:A0A140TAK4 MYD88 UniProt A0A140TAK4 1 EQUAL 296 EQUAL Reactome Database ID Release 82 10265503 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10265503 Reactome R-SSC-193932 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-193932.1 Reactome DB_ID: 10281535 1 IL33:IL1RL1:IL1RAP-1 [plasma membrane] IL33:IL1RL1:IL1RAP-1 Reactome DB_ID: 10281533 1 IL1RL1:IL33 [plasma membrane] IL1RL1:IL33 Reactome DB_ID: 10281531 1 extracellular region GO 0005576 UniProt:K7GS29 IL33 UniProt K7GS29 1 EQUAL 270 EQUAL Reactome DB_ID: 10281527 1 UniProt:A0A287BH51 IL1RL1 UniProt A0A287BH51 19 EQUAL 556 EQUAL Reactome Database ID Release 82 10281533 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10281533 Reactome R-SSC-448601 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-448601.1 Reactome DB_ID: 10281094 1 UniProt:A0A287B9B9 IL1RAP UniProt A0A287B9B9 21 EQUAL 570 EQUAL Reactome Database ID Release 82 10281535 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10281535 Reactome R-SSC-448571 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-448571.1 Reactome Database ID Release 82 10304746 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10304746 Reactome R-SSC-8981947 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8981947.1 Reactome DB_ID: 10281367 1 UniProt:F1RZU1 UniProt F1RZU1 1 EQUAL 712 EQUAL Reactome DB_ID: 10281335 1 UniProt:F6Q7E6 UniProt F6Q7E6 1 EQUAL 460 EQUAL Reactome Database ID Release 82 10304748 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10304748 Reactome R-SSC-8981951 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8981951.1 PIP3 recruits PDPK1 to the membrane PIP3 recruits PDPK1 to the membrane 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: 10267951 1 UniProt:A0A286ZV67 UniProt A0A286ZV67 1 EQUAL 556 EQUAL Reactome DB_ID: 179838 1 Reactome DB_ID: 10256252 1 PDPK1:PIP3 [plasma membrane] PDPK1:PIP3 Reactome DB_ID: 10256250 1 1 EQUAL 556 EQUAL Reactome DB_ID: 179838 1 Reactome Database ID Release 82 10256252 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10256252 Reactome R-SSC-109697 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-109697.1 Reactome Database ID Release 82 10304655 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10304655 Reactome R-SSC-2316429 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2316429.1 PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999). 9895304 Pubmed 1999 Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1 Currie, RA Walker, KS Gray, A Deak, M Casamayor, A Downes, CP Cohen, P Alessi, DR Lucocq, J Biochem J 337:575-83 inferred by electronic annotation IEA GO IEA Negative regulation of the PI3K/AKT network Negative regulation of the PI3K/AKT network This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 3.1.3.67 PTEN dephosphorylates PIP3 PTEN dephosphorylates PIP3 PI(3,4,5)P3 is dephosphorylated to PI (4,5)P2 by PTEN at the plasma membrane 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: 29356 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 179838 1 Reactome DB_ID: 179856 1 Reactome DB_ID: 29372 1 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10266955 UniProt:F2Z5H1 PTEN UniProt F2Z5H1 2 EQUAL 403 EQUAL GO 0016314 GO molecular function Reactome Database ID Release 82 10266956 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10266956 Reactome Database ID Release 82 10266958 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10266958 Reactome R-SSC-199456 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-199456.1 GO 0051898 GO biological process At the plasma membrane, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase aka phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) (Maehama & Dixon 1998, Myers et al. 1998, Das et al. 2003). The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Myers et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase.<br>Early studies indicated that magnesium ion, Mg2+, was needed for the catalytic activity of PTEN isolated from bovine thymus (Kabuyama et al. 1996). Subsequent studies have shown that PTEN was catalytically active in buffers free of magnesium and magnesium was not detected as part of the PTEN crystal (Lee et al. 1999). 12808147 Pubmed 2003 Membrane-binding and activation mechanism of PTEN Das, S Dixon, JE Cho, W Proc Natl Acad Sci U S A 100:7491-6 9811831 Pubmed 1998 The lipid phosphatase activity of PTEN is critical for its tumor supressor function Myers, MP Pass, I Batty, IH van der Kaay, J Stolarov, JP Hemmings, BA Downes, CP Tonks, NK Wigler, Michael H Proc Natl Acad Sci U S A 95:13513-8 10555148 Pubmed 1999 Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association Lee, Jie-Oh Yang, Haijuan Georgescu, Maria-Magdalena Di Cristofano, Antonio Maehama, Tomohiko Shi, Y Dixon, Jack Pandolfi, Pier Pavletich, Nikola Cell 99:323-34 8681945 Pubmed 1996 Purification and characterization of the phosphatidylinositol-3,4,5-trisphosphate phosphatase in bovine thymus Kabuyama, Y Nakatsu, N Homma, Y Fukui, Y Eur. J. Biochem. 238:350-6 9593664 Pubmed 1998 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate Maehama, T Dixon, JE J Biol Chem 273:13375-8 inferred by electronic annotation IEA GO IEA PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling 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> 2.7.1.68 PI4P is phosphorylated to PI(4,5)P2 by PIP5K1A-C at the plasma membrane PI4P is phosphorylated to PI(4,5)P2 by PIP5K1A-C at the plasma membrane 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: 113592 1 Reactome DB_ID: 392417 1 1-phosphatidyl-1D-myo-inositol 4-phosphate [ChEBI:17526] 1-phosphatidyl-1D-myo-inositol 4-phosphate ChEBI 17526 Reactome DB_ID: 179856 1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10296395 PIP5K1A-C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PIP5K1A [cytosol] PIP5K1C [cytosol] PIP5K1B [cytosol] UniProt A0A5G2RDS1 UniProt A0A287AU44 UniProt A0A5G2R3F7 GO 0016308 GO molecular function Reactome Database ID Release 82 10296636 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296636 Reactome Database ID Release 82 10296638 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296638 Reactome R-SSC-1676082 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1676082.1 At the plasma membrane, phosphatidylinositol-4-phosphate 5-kinase type-1 alpha (PIP5K1A), beta (PIP5K1B), and gamma (PIP5K1C) phosphorylate phosphatidylinositol 4-phosphate (PI4P) to produce phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2).<br><br>The following lists the above proteins with their corresponding literature references: PIP5K1A (Halstead et al. 2006, Zhang et al. 1997), PIP5K1B (Zhang et al. 1997), and PIP5K1C (Di Paolo et al. 2002).<br><br>This reaction is of particular interest because its regulation by small GTPases of the RHO and ARF families, not yet annotated here, ties the process of phosphatidylinositol phosphate biosynthesis to regulation of the actin cytoskeleton and vesicular trafficking, and hence to diverse aspects of cell motility and signalling (Oude Weernink et al. 2004, 2007). 17245604 Pubmed 2007 Phospholipase D signaling: orchestration by PIP2 and small GTPases Oude Weernink, PA López de Jesús, M Schmidt, M Naunyn Schmiedebergs Arch Pharmacol 374:399-411 9211928 Pubmed 1997 Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing phosphatidylinositol signaling molecules Zhang, Xiaoxuan Loijens, JC Boronenkov, IV Parker, GJ Norris, FA Chen, J Thum, O Prestwich, GD Majerus, PW Anderson, RA J Biol Chem 272:17756-61 16979564 Pubmed 2006 A role for PtdIns(4,5)P2 and PIP5Kalpha in regulating stress-induced apoptosis Halstead, JR van Rheenen, J Snel, MH Meeuws, S Mohammed, S D'Santos, CS Heck, AJ Jalink, K Divecha, Nullin Curr Biol 16:1850-6 12422219 Pubmed 2002 Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin Di Paolo, G Pellegrini, L Letinic, K Cestra, G Zoncu, R Voronov, S Chang, S Guo, J Wenk, MR De Camilli, Pietro Nature 420:85-9 15464023 Pubmed 2004 Regulation and cellular roles of phosphoinositide 5-kinases Oude Weernink, PA Schmidt, M Jakobs, KH Eur J Pharmacol 500:87-99 inferred by electronic annotation IEA GO IEA 2.7.1.149 PI5P is phosphorylated to PI(4,5)P2 by PIP4K2 dimers at the plasma membrane PI5P is phosphorylated to PI(4,5)P2 by PIP4K2 dimers at the plasma membrane 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: 113592 1 Reactome DB_ID: 1806240 1 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) [ChEBI:57795] 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) 1-phosphatidyl-1D-myo-inositol 5-phosphate trianions 1-phosphatidyl-1D-myo-inositol 5-phosphate trianion 2,3-bis(alkanoyloxy)propyl (1R,2R,3R,4R,5S,6R)-2,3,4,6-tetrahydroxy-5-(phosphonatooxy)cyclohexyl phosphate ChEBI 57795 Reactome DB_ID: 179856 1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10296424 PIP4K2 dimers [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0016309 GO molecular function Reactome Database ID Release 82 10296425 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296425 Reactome Database ID Release 82 10296427 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10296427 Reactome R-SSC-1675776 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1675776.1 At the plasma membrane, phosphatidylinositol-5-phosphate 4-kinase type-2 alpha (PIP4K2A), beta (PIP4K2B) and gamma (PIP4K2C) homodimers and heterodimers (Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015) phosphorylate phosphatidylinositol 5-phosphate (PI5P) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2).<br><br>The following lists the above proteins with their corresponding literature references: PIP4K2A (Rameh et al. 1997, Clarke et al. 2008, Clarke and Irvine 2013), PIP4K2B (Rameh et al. 1997, Clarke and Irvine 2013) and PIP4K2C (Clarke and Irvine 2013, Clarke et al. 2015). 18753295 Pubmed 2008 Localization of phosphatidylinositol phosphate kinase IIgamma in kidney to a membrane trafficking compartment within specialized cells of the nephron Clarke, JH Emson, PC Irvine, RF Am J Physiol Renal Physiol 295:F1422-30 19896968 Pubmed 2010 Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases Clarke, JH Wang, M Irvine, RF Adv Enzyme Regul 50:12-8 23758345 Pubmed 2013 Evolutionarily conserved structural changes in phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) isoforms are responsible for differences in enzyme activity and localization Clarke, Jonathan H Irvine, Robin F Biochem. J. 454:49-57 9367159 Pubmed 1997 A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate Rameh, Lucia Tolias, KF Duckworth, BC Cantley, Lewis C Nature 390:192-6 25495341 Pubmed 2015 The function of phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ) explored using a specific inhibitor that targets the PI5P-binding site Clarke, Jonathan H Giudici, Maria-Luisa Burke, John E Williams, RL Maloney, David J Marugan, Juan Irvine, Robin F Biochem. J. 466:359-67 inferred by electronic annotation IEA GO IEA 2.7.10.2 Inhibition of PP2A activity by phosphorylation of the catalytic subunit at tyrosine Y307 Inhibition of PP2A activity by phosphorylation of the catalytic subunit at tyrosine Y307 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: 113592 1 Reactome DB_ID: 10258704 1 PP2A [cytosol] PP2A Converted from EntitySet in Reactome Reactome DB_ID: 10258702 1 PP2A-catalytic subunit C [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: 10258696 1 PP2A-subunit A [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: 10258690 1 PP2A regulatory subunit B56 [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 82 10258704 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10258704 Reactome R-SSC-196206 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-196206.1 Reactome DB_ID: 29370 1 Reactome DB_ID: 10335066 1 p-Y307-PP2A [cytosol] p-Y307-PP2A Converted from EntitySet in Reactome Reactome DB_ID: 10258696 1 Converted from EntitySet in Reactome Reactome DB_ID: 10335064 1 p-Y307-PP2A-catalytic subunit C [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: 10258690 1 Reactome Database ID Release 82 10335066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10335066 Reactome R-SSC-8857938 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8857938.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10335074 Activated SRC,LCK,EGFR,INSR [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004713 GO molecular function Reactome Database ID Release 82 10335075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10335075 Reactome Database ID Release 82 10335077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10335077 Reactome R-SSC-8857925 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8857925.1 SRC family tyrosine kinases, such as SRC and LCK, as well as receptor tyrosine kinases, such as EGFR and insulin receptor, can phosphorylate the catalytic subunit of serine/threonine protein phosphatase PP2A at tyrosine residue Y307. Phosphorylation at Y307 inhibits the catalytic activity of PP2A. Phosphatidylinositol-5-phosphate (PI5P) positively regulates phosphorylation of the catalytic subunit of PP2A at Y307. 19576174 Pubmed 2009 PtdIns5P protects Akt from dephosphorylation through PP2A inhibition Ramel, Damien Lagarrigue, Frédéric Dupuis-Coronas, Sophie Chicanne, Gaëtan Leslie, Nicholas Gaits-Iacovoni, Frédérique Payrastre, Bernard Tronchère, Hélène Biochem. Biophys. Res. Commun. 387:127-31 1325671 Pubmed 1992 Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation Chen, J Martin, B L Brautigan, D L Science 257:1261-4 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 82 9909778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9909778 Reactome DB_ID: 1806240 IER3 recruits MAPKs to PP2A-B56-beta,gamma IER3 recruits MAPKs to PP2A-B56-beta,gamma IEX1 recruits ERKs to PP2A 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: 10332138 1 PP2A-B56-beta,gamma [cytosol] PP2A-B56-beta,gamma Converted from EntitySet in Reactome Reactome DB_ID: 10258702 1 Converted from EntitySet in Reactome Reactome DB_ID: 10258696 1 Converted from EntitySet in Reactome Reactome DB_ID: 10332136 1 PPP2R5B,PPP2R5C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PPP2R5B [cytosol] PPP2R5C [cytosol] UniProt F1RQR5 UniProt A0A5G2RCB5 Reactome Database ID Release 82 10332138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10332138 Reactome R-SSC-6811526 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-6811526.1 Reactome DB_ID: 10332134 1 UniProt:K7GMQ2 IER3 UniProt K7GMQ2 1 EQUAL 156 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10262377 1 p-T,Y MAPK dimers [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 10332140 1 PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimers [cytosol] PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimers Reactome DB_ID: 10332138 1 Reactome DB_ID: 10332134 1 1 EQUAL 156 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10262377 1 Reactome Database ID Release 82 10332140 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10332140 Reactome R-SSC-6811477 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-6811477.1 Reactome Database ID Release 82 10332155 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10332155 Reactome R-SSC-6811472 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-6811472.1 IER3 (IEX-1) recruits both an activated MAPK (MAPK1 (ERK2) or MAPK3 (ERK1)) and the protein phosphatase 2A (PP2A) complex containing regulatory subunits B56-beta (PPP2R5B) or B56-gamma (PPP2R5C), through an interaction with the B56 subunit, forming a tripartite complex (Letourneux et al. 2006, Rocher et al. 2007). 16456541 Pubmed 2006 B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK Letourneux, C Rocher, G Porteu, F EMBO J 25:727-38 17200115 Pubmed 2007 Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity Rocher, Géraldine Letourneux, Claire Lenormand, Philippe Porteu, Françoise J. Biol. Chem. 282:5468-77 inferred by electronic annotation IEA GO IEA 2.7.11.1 MAPKs phosphorylate PP2A MAPKs phosphorylate PP2A 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: 113592 1 Reactome DB_ID: 10332140 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 10332134 1 1 EQUAL 156 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10332148 1 p-S368-PPP2R5B,p-S337-PPP2R5C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-PPP2R5B [cytosol] phospho-PPP2R5C [cytosol] Reactome DB_ID: 10332150 1 PP2A-A:PP2A-C [cytosol] PP2A-A:PP2A-C Converted from EntitySet in Reactome Reactome DB_ID: 10258702 1 Converted from EntitySet in Reactome Reactome DB_ID: 10258696 1 Reactome Database ID Release 82 10332150 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10332150 Reactome R-SSC-6811485 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-6811485.1 Converted from EntitySet in Reactome Reactome DB_ID: 10262377 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10332140 GO 0004674 GO molecular function Reactome Database ID Release 82 10332151 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10332151 Reactome Database ID Release 82 10332153 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10332153 Reactome R-SSC-6811454 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-6811454.1 Activated MAPK1 (ERK2) or MAPK3 (ERK1), recruited to the PP2A complex through IER3 (IEX-1), phosphorylate the regulatory subunit PPP2R5B (B56-beta) or PPP2R5C (B56-gamma) of the PP2A complex on serine residue S368 or S337, respectively. ERK-mediated phosphorylation of the PP2A regulatory subunits causes dissociation of the PP2A complex and prevents PP2A-mediated dephosphorylation of AKT1 (Letourneux et al. 2006, Rocher et al. 2007). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10351668 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10351668 Reactome R-SSC-6811558 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-6811558.1 GO 0014066 GO biological process Phosphatidylinositol-5-phosphate (PI5P) may modulate PI3K/AKT signaling in several ways. PI5P is used as a substrate for production of phosphatidylinositol-4,5-bisphosphate, PI(4,5)P2 (Rameh et al. 1997, Clarke et al. 2008, Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015), which serves as a substrate for activated PI3K, resulting in the production of PIP3 (Mandelker et al. 2009, Burke et al. 2011). The majority of PI(4,5)P2 in the cell, however, is produced from the phosphatidylinositol-4-phosphate (PI4P) substrate (Zhang et al. 1997, Di Paolo et al. 2002, Oude Weernink et al. 2004, Halstead et al. 2006, Oude Weernink et al. 2007). PIP3 is necessary for the activating phosphorylation of AKT. AKT1 can be deactivated by the protein phosphatase 2A (PP2A) complex that contains a regulatory subunit B56-beta (PPP2R5B) or B56-gamma (PPP2R5C). PI5P inhibits AKT1 dephosphorylation by PP2A through an unknown mechanism (Ramel et al. 2009). Increased PI5P levels correlate with inhibitory phosphorylation(s) of the PP2A complex. MAPK1 (ERK2) and MAPK3 (ERK1) are involved in inhibitory phosphorylation of PP2A, in a process that involves IER3 (IEX-1) (Letourneux et al. 2006, Rocher et al. 2007). It is uncertain, however, whether PI5P is in any way involved in ERK-mediated phosphorylation of PP2A or if it regulates another PP2A kinase. inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10350670 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10350670 Reactome R-SSC-199418 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-199418.1 The PI3K/AKT network is negatively regulated by phosphatases that dephosphorylate PIP3, thus hampering AKT activation. inferred by electronic annotation IEA GO IEA PDPK1 binds PIP2 PDPK1 binds PIP2 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: 179856 1 Reactome DB_ID: 10267951 1 1 EQUAL 556 EQUAL Reactome DB_ID: 10304329 1 PDPK1:PIP2 [plasma membrane] PDPK1:PIP2 Reactome DB_ID: 179856 1 Reactome DB_ID: 10256250 1 1 EQUAL 556 EQUAL Reactome Database ID Release 82 10304329 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10304329 Reactome R-SSC-2219520 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2219520.1 Reactome Database ID Release 82 10304331 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10304331 Reactome R-SSC-2219524 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2219524.1 PDPK1 (PDK1) possesses low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane, in the absence of PI3K activity (Currie et al. 1999). inferred by electronic annotation IEA GO IEA 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> 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: 10339714 1 nucleoplasm GO 0005654 MECOM:PTEN gene [nucleoplasm] MECOM:PTEN gene Reactome DB_ID: 10339712 1 Ghost homologue of PTEN gene [nucleoplasm] Ghost homologue of PTEN gene Reactome DB_ID: 10339708 1 UniProt:A0A480Z2V8 MECOM UniProt A0A480Z2V8 1 EQUAL 1051 EQUAL Reactome Database ID Release 82 10339714 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10339714 Reactome R-SSC-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-SSC-8943810.1 Converted from EntitySet in Reactome Reactome DB_ID: 10339710 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: 10339718 1 MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene Reactome DB_ID: 10339716 1 MECOM:(PRC1.4,PRC2 (EZH2) core) [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core) Converted from EntitySet in Reactome Reactome DB_ID: 10339710 1 Reactome DB_ID: 10339708 1 1 EQUAL 1051 EQUAL Reactome Database ID Release 82 10339716 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10339716 Reactome R-SSC-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-SSC-8943820.1 Reactome DB_ID: 10339712 1 Reactome Database ID Release 82 10339718 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10339718 Reactome R-SSC-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-SSC-8943821.1 Reactome Database ID Release 82 10339720 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10339720 Reactome R-SSC-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-SSC-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. 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 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 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10352406 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10352406 Reactome R-SSC-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-SSC-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). 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 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 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 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 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 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 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 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 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 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 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 inferred by electronic annotation IEA GO IEA Regulation of PTEN localization Regulation of PTEN localization This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PTEN undergoes monoubiquitination PTEN undergoes monoubiquitination This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10249581 1 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity RPS27A [cytosol] UBC [cytosol] UBA52 [cytosol] UniProt A0A287AZA7 UniProt P0CG68 UniProt P63053 Reactome DB_ID: 10266955 1 2 EQUAL 403 EQUAL Reactome DB_ID: 10330614 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: 10330622 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 82 10330623 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330623 Reactome Database ID Release 82 10330625 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330625 Reactome R-SSC-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-SSC-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). 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 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 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: 10330614 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: 10330618 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 82 10330620 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330620 Reactome R-SSC-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-SSC-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 Reactome DB_ID: 10330618 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 Converted from EntitySet in Reactome Reactome DB_ID: 10249097 2 Ub [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity RPS27A [nucleoplasm] UBA52 [nucleoplasm] UBC [nucleoplasm] Reactome DB_ID: 10321392 1 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10307922 UniProt:F1RKZ6 USP7 UniProt F1RKZ6 1 EQUAL 1102 EQUAL GO 0004843 GO molecular function Reactome Database ID Release 82 10307944 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10307944 Reactome Database ID Release 82 10330627 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330627 Reactome R-SSC-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-SSC-6807118.1 USP7 (HAUSP) deubiquitinates monoubiquitinated nuclear PTEN, thus promoting relocalization of PTEN to the cytosol. USP7-mediated deubiquitination of PTEN is negatively regulated by PML in the presence of DAXX, but the exact mechanism has not been elucidated (Song et al. 2008). 18716620 Pubmed 2008 The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network Song, MS Salmena, Leonardo Carracedo, Arkaitz Egia, Ainara Lo-Coco, F Teruya-Feldstein, Julie Pandolfi, Pier Paolo Nature 455:813-7 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 10330628 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330628 Reactome DB_ID: 10307636 UniProt:F1SID1 PML UniProt F1SID1 1 EQUAL 882 EQUAL Deubiquitinated PTEN translocates to the cytosol Deubiquitinated PTEN translocates to the cytosol This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10321392 1 2 EQUAL 403 EQUAL Reactome DB_ID: 10266955 1 2 EQUAL 403 EQUAL Reactome Database ID Release 82 10330630 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330630 Reactome R-SSC-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-SSC-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 82 10352232 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10352232 Reactome R-SSC-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-SSC-8948747.1 When monoubiquitinated by E3 ubiquitin ligases XIAP and NEDD4, PTEN translocates from the cytosol to the nucleus (Trotman et al. 2007, Van Themsche et al. 2009). USP7 (HAUSP)-mediated deubiquitination of monoubiquitinated nuclear PTEN promotes relocalization of PTEN to the cytosol (Song et al. 2008). inferred by electronic annotation IEA GO IEA Regulation of PTEN stability and activity Regulation of PTEN stability and activity This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NEDD4, WWP2, CHIP and XIAP polyubiquitinate PTEN NEDD4, WWP2, CHIP and XIAP polyubiquitinate PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10249581 3 Reactome DB_ID: 10266955 1 2 EQUAL 403 EQUAL Reactome DB_ID: 10330633 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: 10330639 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 STUB1 [cytosol] XIAP [cytosol] WWP2 [cytosol] NEDD4 [cytosol] UniProt A0A287BGG6 UniProt A0A287A6L6 UniProt I3LG84 UniProt A0A287BIE4 Reactome Database ID Release 82 10330640 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330640 Reactome Database ID Release 82 10330642 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330642 Reactome R-SSC-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-SSC-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 MKRN1 polyubiquitinates PTEN MKRN1 polyubiquitinates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10249581 3 Reactome DB_ID: 10266955 1 2 EQUAL 403 EQUAL Reactome DB_ID: 10330645 1 ubiquitinylated lysine (K48polyUb [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10339999 UniProt:A0A287ATB1 MKRN1 UniProt A0A287ATB1 O-phospho-L-serine at 109 (in Homo sapiens) 109 EQUAL O-phospho-L-serine [MOD:00046] 1 EQUAL 482 EQUAL Reactome Database ID Release 82 10340000 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10340000 Reactome Database ID Release 82 10340002 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10340002 Reactome R-SSC-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-SSC-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). 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 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: 10266955 1 2 EQUAL 403 EQUAL Reactome DB_ID: 10340004 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: 10309593 TNKS1/2 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TNKS2 [cytosol] TNKS [cytosol] UniProt F1SCW9 UniProt A0A286ZY03 GO 0003950 GO molecular function Reactome Database ID Release 82 10340005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10340005 Reactome Database ID Release 82 10340007 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10340007 Reactome R-SSC-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-SSC-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: 10340004 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: 10249581 9 Reactome DB_ID: 10333638 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: 10309573 UniProt:A0A287BK85 RNF146 UniProt A0A287BK85 1 EQUAL 359 EQUAL Reactome Database ID Release 82 10340008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10340008 Reactome Database ID Release 82 10340010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10340010 Reactome R-SSC-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-SSC-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: 10333640 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: 10249581 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10249683 26S proteasome [cytosol] 26S proteasome Reactome DB_ID: 10249613 1 UniProt:A1XQU1 PSMB7 UniProt A1XQU1 44 EQUAL 277 EQUAL Reactome DB_ID: 10249619 1 UniProt:F2Z5J1 PSMC1 UniProt F2Z5J1 2 EQUAL 440 EQUAL Reactome DB_ID: 10249639 1 UniProt:F1RKW8 PSMD11 UniProt F1RKW8 2 EQUAL 422 EQUAL Reactome DB_ID: 10249663 1 UniProt:F1SGM3 PSME2 UniProt F1SGM3 2 EQUAL 239 EQUAL Reactome DB_ID: 10249603 1 UniProt:A0A5G2R6J1 PSMB2 UniProt A0A5G2R6J1 1 EQUAL 201 EQUAL Reactome DB_ID: 10249591 1 UniProt:A0A5G2QL81 PSMA4 UniProt A0A5G2QL81 1 EQUAL 261 EQUAL Reactome DB_ID: 10249601 1 UniProt:A0A287BRV0 PSMB10 UniProt A0A287BRV0 40 EQUAL 273 EQUAL Reactome DB_ID: 10249633 1 UniProt:A0A287BG14 PSMC6 UniProt A0A287BG14 1 EQUAL 389 EQUAL Reactome DB_ID: 10249661 1 UniProt:Q64L94 PSME1 UniProt Q64L94 1 EQUAL 249 EQUAL Reactome DB_ID: 10249615 1 Ghost homologue of PSMB8 [cytosol] Ghost homologue of PSMB8 Reactome DB_ID: 10249679 1 UniProt:F1S9C7 PSMB11 UniProt F1S9C7 50 EQUAL 300 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10249631 1 Homologues of PSMC5 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PSMC5 [cytosol] PSMC5 [cytosol] UniProt P62197 UniProt A0A5G2QJH1 Reactome DB_ID: 10249587 1 UniProt:A0A5G2QZH5 PSMA2 UniProt A0A5G2QZH5 2 EQUAL 234 EQUAL Reactome DB_ID: 10249599 1 UniProt:A0A287BPP9 PSMB1 UniProt A0A287BPP9 29 EQUAL 241 EQUAL Reactome DB_ID: 10249649 1 UniProt:A0A288CG47 PSMD4 UniProt A0A288CG47 1 EQUAL 377 EQUAL Reactome DB_ID: 10249605 1 UniProt:A0A286ZN52 PSMB3 UniProt A0A286ZN52 2 EQUAL 205 EQUAL Reactome DB_ID: 10249611 1 UniProt:A0A5G2R4Y9 PSMB6 UniProt A0A5G2R4Y9 35 EQUAL 239 EQUAL Reactome DB_ID: 10249645 1 Ghost homologue of PSMD2 [cytosol] Ghost homologue of PSMD2 Reactome DB_ID: 10249675 1 UniProt:F1SBA5 PSMA8 UniProt F1SBA5 1 EQUAL 256 EQUAL Reactome DB_ID: 10249671 1 UniProt:A0A287APQ3 PSME4 UniProt A0A287APQ3 1 EQUAL 1843 EQUAL Reactome DB_ID: 10249641 1 UniProt:A0A480SMR6 PSMD12 UniProt A0A480SMR6 2 EQUAL 456 EQUAL Reactome DB_ID: 10249585 1 UniProt:A0A5G2QI19 PSMA1 UniProt A0A5G2QI19 1 EQUAL 263 EQUAL Reactome DB_ID: 10249597 1 UniProt:A0A287BRR7 PSMA7 UniProt A0A287BRR7 1 EQUAL 248 EQUAL Reactome DB_ID: 10249617 1 UniProt:Q2PYM7 PSMB9 UniProt Q2PYM7 21 EQUAL 219 EQUAL Reactome DB_ID: 10249621 1 UniProt:F1SB53 PSMC2 UniProt F1SB53 2 EQUAL 433 EQUAL Reactome DB_ID: 10249659 1 UniProt:A0A286ZLP7 PSMD9 UniProt A0A286ZLP7 1 EQUAL 223 EQUAL Reactome DB_ID: 10249653 1 UniProt:F1SGF1 PSMD6 UniProt F1SGF1 1 EQUAL 389 EQUAL Reactome DB_ID: 10249595 1 Ghost homologue of PSMA6 [cytosol] Ghost homologue of PSMA6 Reactome DB_ID: 10249665 1 UniProt:P61291 PSME3 UniProt P61291 2 EQUAL 254 EQUAL Reactome DB_ID: 10249607 1 Ghost homologue of PSMB4 [cytosol] Ghost homologue of PSMB4 Reactome DB_ID: 10249609 1 UniProt:A0A286ZS34 UniProt A0A286ZS34 60 EQUAL 263 EQUAL Reactome DB_ID: 10249657 1 UniProt:A0A287B5Q7 PSMD8 UniProt A0A287B5Q7 1 EQUAL 350 EQUAL Reactome DB_ID: 10249593 1 UniProt:F2Z5K2 PSMA5 UniProt F2Z5K2 1 EQUAL 241 EQUAL Reactome DB_ID: 10249667 1 UniProt:F1S870 PSMF1 UniProt F1S870 1 EQUAL 271 EQUAL Reactome DB_ID: 10249623 1 UniProt:A0A5G2QSU8 PSMC3 UniProt A0A5G2QSU8 1 EQUAL 439 EQUAL Reactome DB_ID: 10249681 1 Ghost homologue of SEM1 [cytosol] Ghost homologue of SEM1 Reactome DB_ID: 10249589 1 UniProt:A0A5G2QWE9 PSMA3 UniProt A0A5G2QWE9 2 EQUAL 255 EQUAL Reactome DB_ID: 10249637 1 UniProt:A0A287BTN9 PSMD10 UniProt A0A287BTN9 1 EQUAL 226 EQUAL Reactome DB_ID: 10249651 1 UniProt:A0A480QIP5 PSMD5 UniProt A0A480QIP5 2 EQUAL 504 EQUAL Reactome DB_ID: 10249625 1 UniProt:A0A287B4P8 PSMC4 UniProt A0A287B4P8 1 EQUAL 418 EQUAL Reactome DB_ID: 10249643 1 UniProt:A0A5G2R6X9 PSMD13 UniProt A0A5G2R6X9 1 EQUAL 376 EQUAL Reactome DB_ID: 10249583 1 UniProt:A0A480DPN6 PSMD14 UniProt A0A480DPN6 1 EQUAL 310 EQUAL Reactome DB_ID: 10249647 1 UniProt:F1RXA7 PSMD3 UniProt F1RXA7 1 EQUAL 534 EQUAL Reactome DB_ID: 10249655 1 UniProt:A0A287AEH0 PSMD7 UniProt A0A287AEH0 1 EQUAL 324 EQUAL Reactome DB_ID: 10249635 1 UniProt:F1SMW9 PSMD1 UniProt F1SMW9 1 EQUAL 953 EQUAL Reactome Database ID Release 82 10249683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10249683 Reactome R-SSC-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-SSC-68819.1 GO 0004175 GO molecular function Reactome Database ID Release 82 10249684 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10249684 Reactome Database ID Release 82 10333642 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10333642 Reactome R-SSC-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-SSC-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: 29356 1 Reactome DB_ID: 10330645 1 ubiquitinylated lysine (K48polyUb [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10249581 3 Reactome DB_ID: 10266955 1 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10330651 USP13,OTUD3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity USP13 [cytosol] OTUD3 [cytosol] UniProt F1SGC5 UniProt A0A287BHA0 Reactome Database ID Release 82 10330652 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330652 Reactome Database ID Release 82 10330654 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10330654 Reactome R-SSC-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-SSC-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: 10332799 1 UniProt:F1RZK6 UniProt F1RZK6 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL O4'-phospho-L-tyrosine [MOD:00048] 1 EQUAL 505 EQUAL Reactome DB_ID: 10266955 1 2 EQUAL 403 EQUAL Reactome DB_ID: 10332801 1 PTEN:p-Y387-FRK [cytosol] PTEN:p-Y387-FRK Reactome DB_ID: 10332799 1 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL 1 EQUAL 505 EQUAL Reactome DB_ID: 10266955 1 2 EQUAL 403 EQUAL Reactome Database ID Release 82 10332801 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10332801 Reactome R-SSC-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-SSC-8847960.1 Reactome Database ID Release 82 10332803 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10332803 Reactome R-SSC-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-SSC-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: 113592 1 Reactome DB_ID: 10332801 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 10332799 1 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL 1 EQUAL 505 EQUAL Reactome DB_ID: 10332806 1 O4'-phospho-L-tyrosine at 336 (in Homo sapiens) 336 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10332801 Reactome Database ID Release 82 10332807 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10332807 Reactome Database ID Release 82 10332809 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10332809 Reactome R-SSC-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-SSC-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: 113592 5 Reactome DB_ID: 10266955 1 2 EQUAL 403 EQUAL Reactome DB_ID: 29370 5 Reactome DB_ID: 10333618 1 O-phospho-L-serine at 370 (in Homo sapiens) 370 EQUAL O-phospho-L-serine at 380 (in Homo sapiens) 380 EQUAL O-phospho-L-threonine at 382 (in Homo sapiens) 382 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-threonine at 383 (in Homo sapiens) 383 EQUAL O-phospho-L-serine at 385 (in Homo sapiens) 385 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10267860 Casein kinase II [cytosol] Casein kinase II Reactome DB_ID: 10267842 2 UniProt:P67872 UniProt P67872 2 EQUAL 215 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10267858 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 Database ID Release 82 10267860 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267860 Reactome R-SSC-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-SSC-201711.1 Reactome Database ID Release 82 10267861 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267861 Reactome Database ID Release 82 10333620 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10333620 Reactome R-SSC-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-SSC-8850945.1 Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. S370 and S385 are the main CK2 phosphorylation sites in PTEN (Torres and Pulido 2001, Miller et al. 2002). CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002). 11035045 Pubmed 2001 The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation Torres, J Pulido, R J. Biol. Chem. 276:993-8 12297295 Pubmed 2002 Direct identification of PTEN phosphorylation sites Miller, Susan J Lou, David Y Seldin, David C Lane, William S Neel, Benjamin G FEBS Lett. 528:145-53 inferred by electronic annotation IEA GO IEA PREX2 binds PTEN and inhibits it PREX2 binds PTEN and inhibits it This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10333626 1 PTEN, p-3S,2T-PTEN [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PTEN [cytosol] phospho-PTEN [cytosol] Reactome DB_ID: 10333624 1 UniProt:A0A286ZSP2 PREX2 UniProt A0A286ZSP2 1 EQUAL 1606 EQUAL Reactome DB_ID: 10333628 1 PREX2:PTEN,p-3S,2T-PTEN [cytosol] PREX2:PTEN,p-3S,2T-PTEN Converted from EntitySet in Reactome Reactome DB_ID: 10333626 1 Reactome DB_ID: 10333624 1 1 EQUAL 1606 EQUAL Reactome Database ID Release 82 10333628 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10333628 Reactome R-SSC-8850934 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8850934.1 Reactome Database ID Release 82 10333630 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10333630 Reactome R-SSC-8850961 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8850961.1 PREX2, a RAC1 guanine nucleotide exchange factor (GEF), binds to PTEN and inhibits its catalytic activity, resulting in enhanced PI3K/AKT signaling (Fine et al. 2009). The interaction involves the inositol polyphosphate 4-phosphatase domain and the pleckstrin homology (PH) domain of PREX2 and the PDZ binding domain, the phosphatase domain and the C2 domain of PTEN (Fine et al. 2009, Hodakoski et al. 2014). PREX2 binds both the unphosphorylated PTEN and PTEN phosphorylated at the C-terminal tail by casein kinase II, but inhibits the lipid phosphatase activity of phosphorylated PTEN only (Hodakoski et al. 2014). The GEF activity of PREX2 is not needed for PTEN inhibition (Fine et al. 2009).<p>PREX2 is frequently overexpressed in breast and prostate cancer (Fine et al. 2009) and mutated in melanoma (Berger et al. 2012). 19729658 Pubmed 2009 Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a Fine, Barry Hodakoski, Cindy Koujak, Susan Su, Tao Saal, Lao H Maurer, Matthew Hopkins, Benjamin Keniry, Megan Sulis, ML Mense, Sarah Hibshoosh, Hanina Parsons, R Science 325:1261-5 22622578 Pubmed 2012 Melanoma genome sequencing reveals frequent PREX2 mutations Berger, Michael F Hodis, Eran Heffernan, Timothy P Deribe, Yonathan Lissanu Lawrence, Michael S Protopopov, Alexei Ivanova, Elena Watson, Ian R Nickerson, Elizabeth Ghosh, Papia Zhang, Hailei Zeid, Rhamy Ren, Xiaojia Cibulskis, K Sivachenko, Andrey Y Wagle, Nikhil Sucker, Antje Sougnez, Carrie Onofrio, R Ambrogio, Lauren Auclair, Daniel Fennell, Timothy Carter, Scott L Drier, Yotam Stojanov, Petar Singer, Meredith A Voet, Douglas Jing, Rui Saksena, Gordon Barretina, Jordi Ramos, AH Pugh, Trevor J Stransky, N Parkin, Melissa Winckler, W Mahan, Scott Ardlie, Kristin Baldwin, Jennifer Wargo, Jennifer Schadendorf, Dirk Meyerson, M Gabriel, Stacey B Golub, Todd R Wagner, Stephan N Lander, Eric S Getz, G Chin, Lynda Garraway, Levi A Nature 485:502-6 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 TRIM27 binds PTEN TRIM27 binds PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10333646 1 UniProt:K7GKN4 TRIM27 UniProt K7GKN4 1 EQUAL 513 EQUAL Reactome DB_ID: 10266955 1 2 EQUAL 403 EQUAL Reactome DB_ID: 10333648 1 PTEN:TRIM27 [cytosol] PTEN:TRIM27 Reactome DB_ID: 10333646 1 1 EQUAL 513 EQUAL Reactome DB_ID: 10266955 1 2 EQUAL 403 EQUAL Reactome Database ID Release 82 10333648 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10333648 Reactome R-SSC-8851000 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8851000.1 Reactome Database ID Release 82 10333650 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10333650 Reactome R-SSC-8850997 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8850997.1 TRIM27 (RFP) binds PTEN. The interaction involves the C-terminal RFP domain of TRIM27 and the C-terminal tail of PTEN (Lee et al. 2013). 23419514 Pubmed 2013 RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation Lee, James T Shan, Jing Zhong, Jiayun Li, Muyang Zhou, Brenda Zhou, Amanda Parsons, R Gu, Wei Cell Res. 23:552-64 inferred by electronic annotation IEA GO IEA TRIM27 polyubiquitinates PTEN TRIM27 polyubiquitinates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10249581 3 Reactome DB_ID: 10333648 1 Reactome DB_ID: 10333653 1 ubiquitinylated lysine (K27polyUb [cytosol]) at unknown position 2 EQUAL 403 EQUAL Reactome DB_ID: 10333646 1 1 EQUAL 513 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10333648 Reactome Database ID Release 82 10333654 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10333654 Reactome Database ID Release 82 10333656 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10333656 Reactome R-SSC-8851011 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8851011.1 TRIM27 (RFP) is an E3 ubiquitin ligase for PTEN. TRIM27 polyubiquitinates PTEN on multiple lysines in the C2 domain of PTEN using K27-linkage between ubiquitin molecules. TRIM27-mediated ubiquitination inhibits PTEN lipid phosphatase activity, but does not affect PTEN protein localization or stability (Lee et al. 2013). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10352236 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10352236 Reactome R-SSC-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-SSC-8948751.1 PTEN protein stability is regulated by ubiquitin ligases, such as NEDD4, WWP2, STUB1 (CHIP), XIAP, MKRN1 and RNF146, which polyubiquitinate PTEN in response to different stimuli and thus target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Maddika et al. 2011, Ahmed et al. 2012, Lee et al. 2015, Li et al. 2015). Several ubiquitin proteases, such as USP13 and OTUD3, can remove polyubiquitin chains from PTEN and rescue it from degradation (Zhang et al. 2013, Yuan et al. 2015). TRIM27 (RFP) is an E3 ubiquitin ligase that polyubiquitinates PTEN on multiple lysines in the C2 domain of PTEN using K27 linkage between ubiquitin molecules. TRIM27 mediated ubiquitination inhibits PTEN lipid phosphatase activity, but does not affect PTEN protein localization or stability (Lee et al. 2013).<br>PTEN phosphorylation by the tyrosine kinase FRK (RAK) inhibits NEDD4 mediated polyubiquitination and subsequent degradation of PTEN, thus increasing PTEN half life. FRK mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase 2 (CK2) mediated phosphorylation of the C-terminus of PTEN on multiple serine and threonine residues increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).<br>PREX2, a RAC1 guanine nucleotide exchange factor (GEF) can binds to PTEN and inhibit its catalytic activity (Fine et al. 2009). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10352234 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10352234 Reactome R-SSC-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-SSC-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). 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 18757404 Pubmed 2008 PTEN acetylation modulates its interaction with PDZ domain Ikenoue, T Inoki, Ken Zhao, B Guan, KL Cancer Res. 68:6908-12 24429633 Pubmed 2014 The multilayered complexity of ceRNA crosstalk and competition Tay, Yvonne Rinn, John Pandolfi, Pier Paolo Nature 505:344-52 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 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10349994 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349994 Reactome R-SSC-1257604 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1257604.1 Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007. 17604717 Pubmed 2007 AKT/PKB signaling: navigating downstream Manning, BD Cantley, Lewis C Cell 129:1261-74 inferred by electronic annotation IEA GO IEA