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: 10750486 1 plasma membrane GO 0005886 RAC1:GTP [plasma membrane] RAC1:GTP Reactome DB_ID: 29438 1 cytosol GO 0005829 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) Reactome http://www.reactome.org ChEBI 37565 Reactome DB_ID: 10750484 1 UniProt:Q03206 ced-10 ced-10 ced-10 C09G12.8 rac-1 FUNCTION Required in engulfing to control the phagocytosis of apoptotic cell corpses (PubMed:10707082, PubMed:20126385). Required in embryonic development for the correct positioning and orientation of the mitotic spindles and division planes in blastomere cells (PubMed:20126385). Involved in hypodermal cell fusion, together with pak-1 and cdc-42, leading to embryonic body elongation, which involves dramatic cytoskeletal reorganization (PubMed:8824291). ced-2 and ced-5 function to activate ced-10 in a GTPase signaling pathway that controls the polarized extension of cell surfaces (PubMed:10707082). Plays a redundant role with mig-2 in dorsal axonal guidance in ventral cord commissural motoneurons and in P neuroblast migration. May regulate these 2 processes by activating pak-1 and/or max-2 (PubMed:17050621). Plays a role, probably via mig-10, in orientating axonal growth of HSN and AVM neurons in response to guidance cues such as slt-1. Regulates mig-10 asymmetric distribution in HSN neurons (PubMed:18499456). During the dorso-ventral axonal guidance and outgrowth of VD neurons, required together with mig-2 to inhibit growth cone filopodial protrusion mediated by netrin guidance cue unc-6 and its receptors unc-5 and unc-40 (PubMed:25371370, PubMed:30045855). Specifically, regulates growth cone filopodial protrusion polarity, and thus migration, by promoting F-actin polarization and, together with mig-2, by restricting plus-end microtubule accumulation in the growth cone (PubMed:30045855). Plays a role in protecting dopaminergic neurons from oxidative stress-induced degeneration (PubMed:29346382). During gonad morphogenesis, plays a role in distal tip cell (DTC)-mediated guidance of gonad elongation, probably by activating max-2 (PubMed:19797046, PubMed:19023419). Furthermore, plays a role in distal tip cell polarity and migration by negatively regulating the unc-6/Netrin receptor unc-5 (PubMed:26292279). May be involved in signal transduction during cell migration (PubMed:10707082). May be involved in the positioning of ray 1, the most anterior ray sensilium, in the male tail (PubMed:24004945).SUBUNIT Interacts (GTP-bound form) with pak-1 (PubMed:8824291). May interact (GTP-bound form) with mig-10 (via Ras-associating and PH domains) (PubMed:18499456).TISSUE SPECIFICITY Colocalizes with pak-1 to hypodermal cell boundaries during embryo elongation throughout the second phase of embryogenesis.DEVELOPMENTAL STAGE Most abundant at embryonic stage, its expression decreases dramatically during development.DISRUPTION PHENOTYPE In the second generation, there is defective mitotic spindle orientation in the EMS and ABar blastomeres which results in disrupted left-right asymmetry and failure to undergo morphogenesis (PubMed:20126385). Due to defective apoptotic cell clearance, embryos accumulate apoptotic cell corpses (PubMed:20126385). Distal tip cell migratory defects (PubMed:26292279). Double knockout with unc-5 RNAi suppresses the distal tip cell migratory defect in the ced-10 single mutant (PubMed:26292279).SIMILARITY Belongs to the small GTPase superfamily. Rho family. Caenorhabditis elegans NCBI Taxonomy 6239 UniProt Q03206 Chain Coordinates 1 EQUAL 189 EQUAL Reactome Database ID Release 82 10750486 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10750486 Reactome R-CEL-442641 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-442641.1 Reactome DB_ID: 10748449 1 PI3K [cytosol] PI3K Reactome DB_ID: 10748447 1 UniProt:Q94125 age-1 UniProt Q94125 1 EQUAL 1068 EQUAL Reactome DB_ID: 10748440 1 UniProt:G5EDP9 aap-1 UniProt G5EDP9 1 EQUAL 724 EQUAL Reactome Database ID Release 82 10748449 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10748449 Reactome R-CEL-74693 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-74693.1 Reactome DB_ID: 10750490 1 RAC1:GTP,RAC2:GTP,RHOG:GTP:PI3K alpha [plasma membrane] RAC1:GTP,RAC2:GTP,RHOG:GTP:PI3K alpha Reactome DB_ID: 10750486 1 Reactome DB_ID: 10748449 1 Reactome Database ID Release 82 10750490 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10750490 Reactome R-CEL-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-CEL-114540.1 Reactome Database ID Release 82 10750492 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10750492 Reactome R-CEL-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-CEL-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: 10783895 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 10783896 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783896 Reactome Database ID Release 82 10783898 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783898 Reactome R-CEL-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-CEL-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 PIP3 recruits AKT to the membrane PIP3 recruits AKT 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> Converted from EntitySet in Reactome Reactome DB_ID: 10763526 1 AKT [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AKT1 [cytosol] AKT1 [cytosol] UniProt Q17941 UniProt Q9XTG7 Reactome DB_ID: 179838 1 Reactome DB_ID: 10756099 1 AKT:PIP3 [plasma membrane] AKT:PIP3 Converted from EntitySet in Reactome Reactome DB_ID: 10756097 1 AKT [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AKT1 [plasma membrane] AKT1 [plasma membrane] Reactome DB_ID: 179838 1 Reactome Database ID Release 82 10756099 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756099 Reactome R-CEL-2317329 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-2317329.1 Reactome Database ID Release 82 10783904 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783904 Reactome R-CEL-2317332 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-2317332.1 GO 0032148 GO biological process PIP3 generated by PI3K recruits AKT (also known as protein kinase B) to the membrane, through its PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation (Scheid et al. 2002). In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied. 17914025 Pubmed 2008 The role of Akt in the signaling pathway of the glycoprotein Ib-IX induced platelet activation Yin, H Stojanovic, A Hay, N Du, X Blood 111:658-65 12167717 Pubmed 2002 Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B Scheid, MP Marignani, PA Woodgett, JR Mol Cell Biol 22:6247-60 2008 The role of Akt3 in Platelet Activation O'Brien, K Stojanovic, A Hay, N Du, X Arteriosclerosis, Thrombosis, and Vascular Biology 28:e162 inferred by electronic annotation IEA GO IEA 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: 10757271 1 UniProt:Q9UA62 UniProt Q9UA62 1 EQUAL 556 EQUAL Reactome DB_ID: 179838 1 Reactome DB_ID: 10749565 1 PDPK1:PIP3 [plasma membrane] PDPK1:PIP3 Reactome DB_ID: 10749563 1 1 EQUAL 556 EQUAL Reactome DB_ID: 179838 1 Reactome Database ID Release 82 10749565 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10749565 Reactome R-CEL-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-CEL-109697.1 Reactome Database ID Release 82 10783844 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783844 Reactome R-CEL-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-CEL-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 2.7.11.1 TORC2 (mTOR) phosphorylates AKT at S473 TORC2 (mTOR) phosphorylates AKT at S473 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: 10756099 1 Reactome DB_ID: 10756117 1 p-S-AKT:PIP3 [plasma membrane] p-S-AKT:PIP3 Converted from EntitySet in Reactome Reactome DB_ID: 10756115 1 p-S-AKT [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-S473-AKT1 [plasma membrane] phospho-p-S473-AKT1 [plasma membrane] Reactome DB_ID: 179838 1 Reactome Database ID Release 82 10756117 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756117 Reactome R-CEL-2317310 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-2317310.1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10756131 TORC2 complex [cytosol] TORC2 complex Reactome DB_ID: 10756127 1 UniProt:Q9NA80 sinh-1 UniProt Q9NA80 2 EQUAL 522 EQUAL Reactome DB_ID: 10756122 1 UniProt:G5EFN2 rict-1 UniProt G5EFN2 1 EQUAL 1708 EQUAL Reactome DB_ID: 10751786 1 UniProt:Q95Q95 let-363 UniProt Q95Q95 1 EQUAL 2549 EQUAL Reactome DB_ID: 10756129 1 Ghost homologue of PRR5 [cytosol] Ghost homologue of PRR5 Reactome DB_ID: 10751781 1 UniProt:P91040 mlst-8 UniProt P91040 1 EQUAL 326 EQUAL Reactome Database ID Release 82 10756131 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756131 Reactome R-CEL-198626 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-198626.1 GO 0004674 GO molecular function Reactome Database ID Release 82 10756132 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756132 Reactome Database ID Release 82 10756138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756138 Reactome R-CEL-198640 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-198640.1 Under conditions of growth and mitogen stimulation S473 phosphorylation of AKT is carried out by mTOR (mammalian Target of Rapamycin). This kinase is found in two structurally and functionally distinct protein complexes, named TOR complex 1 (TORC1) and TOR complex 2 (TORC2). It is TORC2 complex, which is composed of mTOR, RICTOR, SIN1 (also named MAPKAP1) and LST8, that phosphorylates AKT at S473 (Sarbassov et al., 2005). This complex also regulates actin cytoskeletal reorganization (Jacinto et al., 2004; Sarbassov et al., 2004). TORC1, on the other hand, is a major regulator of ribosomal biogenesis and protein synthesis (Hay and Sonenberg, 2004). TORC1 regulates these processes largely by the phosphorylation/inactivation of the repressors of mRNA translation 4E binding proteins (4E BPs) and by the phosphorylation/activation of ribosomal S6 kinase (S6K1). TORC1 is also the principal regulator of autophagy. In other physiological conditions, other kinases may be responsible for AKT S473 phosphorylation.<br> Phosphorylation of AKT on S473 by TORC2 complex is a prerequisite for AKT phosphorylation on T308 by PDPK1 (Scheid et al. 2002, Sarabassov et al. 2005). 19303758 Pubmed 2009 PIKKing on PKB: regulation of PKB activity by phosphorylation Bozulic, L Hemmings, BA Curr Opin Cell Biol 21:256-61 15268862 Pubmed 2004 Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton Sarbassov, DD Ali, SM Kim, DH Guertin, DA Latek, RR Erdjument-Bromage, H Tempst, P Sabatini, DM Curr Biol 14:1296-302 15467718 Pubmed 2004 Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive Jacinto, E Loewith, R Schmidt, A Lin, S Ruegg, MA Hall, A Hall, MN Nat Cell Biol 6:1122-8 15314020 Pubmed 2004 Upstream and downstream of mTOR Hay, N Sonenberg, Nahum Genes Dev 18:1926-45 15718470 Pubmed 2005 Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex Sarbassov, DD Guertin, DA Ali, SM Sabatini, DM Science 307:1098-101 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 10756139 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756139 Reactome DB_ID: 10756136 AKT:PIP3:THEM4/TRIB3 [plasma membrane] AKT:PIP3:THEM4/TRIB3 Reactome DB_ID: 10756134 1 UniProt:G5EED4 UniProt G5EED4 1 EQUAL 358 EQUAL Reactome DB_ID: 10756099 1 Reactome Database ID Release 82 10756136 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756136 Reactome R-CEL-199453 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-199453.1 AKT binds PDPK1 AKT binds PDPK1 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: 10756117 1 Reactome DB_ID: 10749565 1 Reactome DB_ID: 10783900 1 p-S-AKT:PDPK1:PIP3 [plasma membrane] p-S-AKT:PDPK1:PIP3 Reactome DB_ID: 10756117 1 Reactome DB_ID: 10749565 1 Reactome Database ID Release 82 10783900 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783900 Reactome R-CEL-2317313 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-2317313.1 Reactome Database ID Release 82 10783902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783902 Reactome R-CEL-2317314 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-2317314.1 Once phosphorylated on serine residue S473, AKT bound to PIP3 forms a complex with PIP3-bound PDPK1 i.e. PDK1 (Scheid et al. 2002, Sarabassov et al. 2005) inferred by electronic annotation IEA GO IEA AKT phosphorylates targets in the cytosol AKT phosphorylates targets in 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> 2.7.11.1 AKT phosphorylates p21Cip1 and p27Kip1 AKT phosphorylates p21Cip1 and p27Kip1 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 Converted from EntitySet in Reactome Reactome DB_ID: 10754540 1 Homologues of CDKN1B [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity cki-1 [cytosol] cki-2 [cytosol] UniProt Q22197 UniProt G5EEJ2 Converted from EntitySet in Reactome Reactome DB_ID: 10756062 1 Homologues of p-T157-CDKN1B [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-cki-2 [cytosol] phospho-cki-1 [cytosol] Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10756078 p-T,p-S-AKT [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-T308,S473-AKT1 [cytosol] phospho-p-T308,S473-AKT1 [cytosol] Reactome Database ID Release 82 10756079 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756079 Reactome Database ID Release 82 10756081 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756081 Reactome R-CEL-198613 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-198613.1 GO 0043491 GO biological process Phosphorylation of p27Kip1 at T157 and of p21Cip1 at T145 by AKT leads to their retention in the cytoplasm, segregating these cyclin-dependent kinase (CDK) inhibitors from cyclin-CDK complexes. 12244303 Pubmed 2002 Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer Viglietto, G Motti, ML Bruni, P Melillo, RM D'Alessio, A Califano, D Vinci, F Chiappetta, G Tsichlis, P Bellacosa, A Fusco, A Santoro, M Nat Med 8:1136-44 11231573 Pubmed 2001 Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells Zhou, B P Liao, Y Xia, W Spohn, B Lee, M H Hung, M C Nat. Cell Biol. 3:245-52 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT phosphorylates MKRN1 AKT phosphorylates MKRN1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 10774237 1 UniProt:Q9N373 lep-2 UniProt Q9N373 1 EQUAL 482 EQUAL Reactome DB_ID: 29370 1 Reactome DB_ID: 10811126 1 O-phospho-L-serine at 109 (in Homo sapiens) 109 EQUAL O-phospho-L-serine [MOD:00046] 1 EQUAL 482 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10756078 Reactome Database ID Release 82 10811128 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10811128 Reactome R-CEL-8948757 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8948757.1 AKT1 (and possibly AKT2 and AKT3), activated in response to EGF treatment, phosphorylates MKRN1, an E3 ubiquitin ligase, on serine residue S109. AKT-mediated phosphorylation results in stabilization of MKRN1, protecting it from ubiquitination and proteasome-mediated degradation (Lee et al. 2015). 26183061 Pubmed 2015 PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis Lee, Min-Sik Jeong, Man-Hyung Lee, Hyun-Woo Han, Hyun-Ji Ko, Aram Hewitt, SM Kim, Jae-Hoon Chun, Kyung-Hee Chung, Joon-Yong Lee, Cheolju Cho, Hanbyoul Song, Jaewhan Nat Commun 6:7769 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10817381 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10817381 Reactome R-CEL-198323 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-198323.1 Following activation, AKT can phosphorylate an array of target proteins in the cytoplasm, many of which are involved in cell survival control. Phosphorylation of TSC2 feeds positively to the TOR kinase, which, in turn, contributes to AKT activation (positive feedback loop). inferred by electronic annotation IEA GO IEA AKT phosphorylates targets in the nucleus AKT phosphorylates targets in 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> 2.7.11.1 AKT phosphorylates CREB1 AKT phosphorylates CREB1 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: 29358 1 nucleoplasm GO 0005654 Reactome DB_ID: 10756361 1 UniProt:D0Z5N1 crh-1 UniProt D0Z5N1 1 EQUAL 341 EQUAL Reactome DB_ID: 10756364 1 O-phospho-L-serine at 133 (in Homo sapiens) 133 EQUAL 1 EQUAL 341 EQUAL Reactome DB_ID: 113582 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10756380 p-T,p-S-AKT [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-T308,S473-AKT1 [nucleoplasm] phospho-p-T308,S473-AKT1 [nucleoplasm] Reactome Database ID Release 82 10756381 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756381 Reactome Database ID Release 82 10756383 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756383 Reactome R-CEL-199298 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-199298.1 AKT phosphorylates CREB (cAMP response element-binding protein) at serine 133 and activates gene expression via a CREB-dependent mechanism, thus promoting cell survival. 9829964 Pubmed 1998 CREB is a regulatory target for the protein kinase Akt/PKB Du, K Montminy, M J Biol Chem 273:32377-9 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT phosphorylates FOXO transcription factors AKT phosphorylates FOXO transcription factors 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: 10756388 1 UniProt:O16850 daf-16 UniProt O16850 1 EQUAL 655 EQUAL Reactome DB_ID: 29358 3 Reactome DB_ID: 10756399 1 O-phospho-L-threonine at 24 (in Homo sapiens) 24 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-serine at 256 (in Homo sapiens) 256 EQUAL O-phospho-L-serine at 319 (in Homo sapiens) 319 EQUAL 1 EQUAL 655 EQUAL Reactome DB_ID: 113582 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10756380 Reactome Database ID Release 82 10756414 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756414 Reactome R-CEL-199299 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-199299.1 AKT-mediated phosphorylation of Forkhead box (FOX) transcription factors of the FOXO family, FOXO1 (FKHR), FOXO3 (FoxO3a, also known as FKHRL1) and FOXO4 (AFX) contributes to PI3K/AKT signaling-stimulated cell survival and growth. Activated AKT1 phosphorylates FOXO1 on threonine residue T24 and serine residues S256 and S319 (Rena et al. 1999), FOXO3 on threonine residue T32 and serine residues S253 and S315 (Brunet et al. 1999), and FOXO4 on threonine residue T32 and serine residues S197 and S262 (Kops et al. 1999).<br>Based on studies with recombinant mouse Foxo6 expressed in the human embryonic kidney cell line HEK293, FOXO6 has two conserved AKT phosphorylation sites: T26 and S184. Mouse Foxo6 has a third predicted Akt phosphorylation site at the C-terminus, T338, which is not present in other Foxo family members and is not conserved in human FOXO6. T26 and S184 are phosphorylated in response to growth factors known to activate PI3K/AKT signaling, but AKT has not been explicitly identified as the responsible kinase. In contrast to other FOXO family members, FOXO6 remains predominantly nuclear irrespective of growth factor-induced signaling, and only a small portion of phosphorylated FOXO6 may shuttle to the cytosol. Phosphorylation of FOXO6 on putative AKT sites, however, may inhibit binding of FOXO6 to target DNA sites (Jacobs et al. 2003, van der Heide et al. 2005).<br>Protein phosphatase DUSP6 (MKP3) may act to dephosphorylate FOXO1 after AKT-mediated phosphorylation (Rodrigues et al. 2017). 10358075 Pubmed 1999 Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B Rena, G Guo, S Cichy, SC Unterman, TG Cohen, P J Biol Chem 274:17179-83 12857750 Pubmed 2003 FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics Jacobs, Frank M J van der Heide, Lars P Wijchers, Patrick J E C Burbach, J Peter H Hoekman, Marco F M Smidt, Marten P J. Biol. Chem. 278:35959-67 10102273 Pubmed 1999 Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor Brunet, A Bonni, A Zigmond, MJ Lin, MZ Juo, P Hu, LS Anderson, MJ Arden, KC Blenis, J Greenberg, ME Cell 96:857-68 15987244 Pubmed 2005 FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling van der Heide, Lars P Jacobs, Frank M J Burbach, J Peter H Hoekman, Marco F M Smidt, Marten P Biochem. J. 391:623-9 28866049 Pubmed 2017 Overexpression of Mitogen-activated protein kinase phosphatase-3 (MKP-3) reduces FoxO1 phosphorylation in mice hypothalamus Rodrigues, Bárbara de Almeida Kuga, Gabriel Keine Muñoz, Vitor Rosetto Gaspar, Rafael Calais Tavares, Mariana Rosolen Botezelli, José Diego da Silva, Adelino Sanchez Ramos Cintra, Dennys Esper de Moura, Leandro Pereira Simabuco, Fernando Moreira Ropelle, Eduardo Rochete Pauli, José Rodrigo Neurosci. Lett. 659:14-17 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT can phosphorylate RSK AKT can phosphorylate RSK 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: 10756487 1 Homologues of RPS6KB2 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity RPS6KB2 [nucleoplasm] RPS6KB2 [nucleoplasm] UniProt Q9NAH6 UniProt Q21694 Reactome DB_ID: 29358 2 Reactome DB_ID: 113582 2 Converted from EntitySet in Reactome Reactome DB_ID: 10756497 1 Homologues of p-S15,S356-RPS6KB2 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-S15,S356-RPS6KB2 [nucleoplasm] phospho-p-S15,S356-RPS6KB2 [nucleoplasm] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10756380 Reactome Database ID Release 82 10756499 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756499 Reactome R-CEL-199839 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-199839.1 Ribosomal protein S6 kinase beta-2 (RSK) activation is a highly conserved mitogenic response, and the activities of RSK are stimulated by multiple serine/threonine phosphorylations by different upstream kinases, one of which is AKT. 10490848 Pubmed 1999 Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); a novel nuclear target of Akt Koh, H Jee, K Lee, B Kim, J Kim, D Yun, YH Kim, JW Choi, HS Chung, J Oncogene 18:5115-9 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT can phosphorylate NR4A1 (NUR77) AKT can phosphorylate NR4A1 (NUR77) 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: 10756504 1 UniProt:P41829 nhr-6 UniProt P41829 1 EQUAL 598 EQUAL Reactome DB_ID: 29358 1 Reactome DB_ID: 10756507 1 O-phospho-L-serine at 351 (in Homo sapiens) 351 EQUAL 1 EQUAL 598 EQUAL Reactome DB_ID: 113582 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10756380 Reactome Database ID Release 82 10756509 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756509 Reactome R-CEL-199863 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-199863.1 AKT inhibits DNA binding of NUR77 and inhibits its pro-apoptotic function (PMID 11438550). However, the relevance of AKT for NUR77 phosphorylation has recently been questioned: according to recent work, NUR77 is phosphorylated by RSK (and MSK) rather than by AKT (PMID 16223362). 11274386 Pubmed 2001 Akt phosphorylates and regulates the orphan nuclear receptor Nur77 Pekarsky, Y Hallas, C Palamarchuk, A Koval, A Bullrich, F Hirata, Y Bichi, R Letofsky, J Croce, CM Proc Natl Acad Sci U S A 98:3690-4 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10817405 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10817405 Reactome R-CEL-198693 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-198693.1 After translocation into the nucleus, AKT can phosphorylate a number of targets there such as CREB, forkhead transcription factors, SRK and NUR77. 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> THEM4 (CTMP) and/or TRIB3 inhibit AKT phosphorylation THEM4 (CTMP) and/or TRIB3 inhibit AKT phosphorylation 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: 10756134 1 1 EQUAL 358 EQUAL Reactome DB_ID: 10756099 1 Reactome DB_ID: 10756136 1 Reactome Database ID Release 82 10756444 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756444 Reactome R-CEL-199443 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-199443.1 GO 0051898 GO biological process The phosphorylation of membrane-recruited AKT at threonine and serine can be inhibited by direct binding of two different proteins, C-terminal modulator protein (THEM4 i.e. CTMP), which binds to the carboxy-terminal tail of AKT (Maira et al. 2001), or Tribbles homolog 3 (TRIB3), which binds to the catalytic domain of AKT (Du et al. 2003). 11598301 Pubmed 2001 Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane Maira, SM Galetic, I Brazil, DP Kaech, S Ingley, E Thelen, M Hemmings, BA Science 294:374-80 12791994 Pubmed 2003 TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver Du, K Herzig, S Kulkarni, RN Montminy, M Science 300:1574-7 inferred by electronic annotation IEA GO IEA 3.1.3.16 PHLPP dephosphorylates S473 in AKT PHLPP dephosphorylates S473 in AKT 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: 10756078 1 Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Converted from EntitySet in Reactome Reactome DB_ID: 10756430 1 p-T-AKT [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-T308-AKT1 [cytosol] phospho-p-T308-AKT1 [cytosol] 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: 10756439 PHLPP (Mn2+ cofactor) [cytosol] PHLPP (Mn2+ cofactor) Reactome DB_ID: 10756435 1 UniProt:Q09564 phlp-2 UniProt Q09564 1 EQUAL 1717 EQUAL Reactome DB_ID: 29418 2 manganese(2+) [ChEBI:29035] manganese(2+) manganese(II) manganous ion MANGANESE (II) ION manganese, ion (Mn2+) Mn(2+) ChEBI 29035 Reactome Database ID Release 82 10756439 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756439 Reactome R-CEL-199450 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-199450.1 GO 0004722 GO molecular function Reactome Database ID Release 82 10756440 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756440 Reactome Database ID Release 82 10756442 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10756442 Reactome R-CEL-199425 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-199425.1 The PH domain leucine-rich repeat-containing protein phosphatases, PHLPP1 (Gao et al. 2005) and PHLPP2 (Brognard et al. 2007) can specifically dephosphorylate the serine residue and inactivate AKT. 17386267 Pubmed 2007 PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms Brognard, John Sierecki, Emma Gao, Tianyan Newton, Alexandra C Mol. Cell 25:917-31 15808505 Pubmed 2005 PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth Gao, T Furnari, F Newton, AC Mol Cell 18:13-24 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 Reactome DB_ID: 10779844 UniProt:O01759 ppk-1 UniProt O01759 1 EQUAL 562 EQUAL GO 0016308 GO molecular function Reactome Database ID Release 82 10780019 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10780019 Reactome Database ID Release 82 10780021 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10780021 Reactome R-CEL-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-CEL-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: 10779872 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 10779873 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10779873 Reactome Database ID Release 82 10779875 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10779875 Reactome R-CEL-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-CEL-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 3.1.3.16 AKT1 dephosphorylation by PP2A-B56-beta,gamma AKT1 dephosphorylation by PP2A-B56-beta,gamma 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 2 Converted from EntitySet in Reactome Reactome DB_ID: 10756072 1 Homologues of p-T308,S473-AKT1 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-T308,S473-AKT1 [cytosol] phospho-p-T308,S473-AKT1 [cytosol] Converted from EntitySet in Reactome Reactome DB_ID: 10763522 1 Homologues of AKT1 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AKT1 [cytosol] AKT1 [cytosol] Reactome DB_ID: 29372 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10806016 PP2A-B56-beta,gamma [cytosol] PP2A-B56-beta,gamma Converted from EntitySet in Reactome Reactome DB_ID: 10755738 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: 10806014 1 PPP2R5B,PPP2R5C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity pptr-2 [cytosol] pptr-1 [cytosol] UniProt A9UJN4 UniProt O18178 Converted from EntitySet in Reactome Reactome DB_ID: 10755734 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 Reactome Database ID Release 82 10806016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10806016 Reactome R-CEL-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-CEL-6811526.1 Reactome Database ID Release 82 10806019 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10806019 Reactome Database ID Release 82 10806021 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10806021 Reactome R-CEL-6811504 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-6811504.1 The protein phosphatase 2A (PP2A) complex containing a regulatory subunit B56 beta (PPP2R5B) or B56 gamma (PPP2R5C) dephosphorylates activated AKT1 on threonine residue T308 and serine residue S473, thus halting PI3K/AKT signaling (Rocher et al. 2007). Phosphatidylinositol-5-phosphate (PI5P) negatively regulates PP2A-mediated dephosphorylation of AKT1 by promoting, through an unknown mechanism, an inhibitory phosphorylation on tyrosine residue Y307 (Chen et al. 1992) of the catalytic subunit of PP2A (Ramel et al. 2009). 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 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 INHIBITION Reactome Database ID Release 82 9906825 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9906825 Reactome DB_ID: 1806240 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: 10755740 1 PP2A [cytosol] PP2A Converted from EntitySet in Reactome Reactome DB_ID: 10755728 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 Converted from EntitySet in Reactome Reactome DB_ID: 10755738 1 Converted from EntitySet in Reactome Reactome DB_ID: 10755734 1 Reactome Database ID Release 82 10755740 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10755740 Reactome R-CEL-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-CEL-196206.1 Reactome DB_ID: 29370 1 Reactome DB_ID: 10807766 1 p-Y307-PP2A [cytosol] p-Y307-PP2A Converted from EntitySet in Reactome Reactome DB_ID: 10755728 1 Converted from EntitySet in Reactome Reactome DB_ID: 10755734 1 Converted from EntitySet in Reactome Reactome DB_ID: 10807764 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 Reactome Database ID Release 82 10807766 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10807766 Reactome R-CEL-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-CEL-8857938.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10807775 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 10807776 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10807776 Reactome Database ID Release 82 10807778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10807778 Reactome R-CEL-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-CEL-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. 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 Reactome Database ID Release 82 10818159 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10818159 Reactome R-CEL-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-CEL-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. 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 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10817419 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10817419 Reactome R-CEL-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-CEL-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: 10757271 1 1 EQUAL 556 EQUAL Reactome DB_ID: 10783840 1 PDPK1:PIP2 [plasma membrane] PDPK1:PIP2 Reactome DB_ID: 10749563 1 1 EQUAL 556 EQUAL Reactome DB_ID: 179856 1 Reactome Database ID Release 82 10783840 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783840 Reactome R-CEL-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-CEL-2219520.1 Reactome Database ID Release 82 10783842 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783842 Reactome R-CEL-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-CEL-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> SALL4 recruits NuRD to PTEN gene SALL4 recruits NuRD to PTEN gene This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10810880 1 NuRD complex [nucleoplasm] NuRD complex Reactome DB_ID: 10810865 1 Ghost homologue of MBD3 [nucleoplasm] Ghost homologue of MBD3 Converted from EntitySet in Reactome Reactome DB_ID: 10810863 1 Mi-2 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CHD4 [nucleoplasm] CHD4 [nucleoplasm] CHD3 [nucleoplasm] CHD3 [nucleoplasm] UniProt Q22516 UniProt G5EBZ4 Converted from EntitySet in Reactome Reactome DB_ID: 10810878 1 (GATAD2A, GATAD2B) [nucleoplasm] 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: 10776419 1 Homologues of RBBP4 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity rba-1 [nucleoplasm] lin-53 [nucleoplasm] UniProt P90917 UniProt P90916 Reactome DB_ID: 10810843 1 HDAC1:HDAC2 [nucleoplasm] HDAC1:HDAC2 Converted from EntitySet in Reactome Reactome DB_ID: 10788486 1 Homologues of HDAC2 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity HDAC2 [nucleoplasm] hda-1 [nucleoplasm] UniProt G5ECH0 UniProt O17695 Reactome DB_ID: 10775501 1 UniProt:O17695 hda-1 1 EQUAL 482 EQUAL Reactome Database ID Release 82 10810843 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10810843 Reactome R-CEL-4657004 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-4657004.1 Reactome DB_ID: 10776412 1 UniProt:P90916 lin-53 2 EQUAL 425 EQUAL Reactome DB_ID: 10787192 1 UniProt:O61907 lin-40 UniProt O61907 1 EQUAL 715 EQUAL Reactome Database ID Release 82 10810880 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10810880 Reactome R-CEL-4657018 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-4657018.1 Reactome DB_ID: 10810841 1 SALL4:PTEN gene [nucleoplasm] SALL4:PTEN gene Reactome DB_ID: 10810839 1 Ghost homologue of PTEN gene [nucleoplasm] Ghost homologue of PTEN gene Reactome DB_ID: 10785629 1 UniProt:G5EFF4 sem-4 UniProt G5EFF4 1 EQUAL 1053 EQUAL Reactome Database ID Release 82 10810841 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10810841 Reactome R-CEL-8943729 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8943729.1 Reactome DB_ID: 10810884 1 SALL4:NuRD:PTEN gene [nucleoplasm] SALL4:NuRD:PTEN gene Reactome DB_ID: 10810839 1 Reactome DB_ID: 10810882 1 SALL4:NuRD [nucleoplasm] SALL4:NuRD Reactome DB_ID: 10785629 1 1 EQUAL 1053 EQUAL Reactome DB_ID: 10810880 1 Reactome Database ID Release 82 10810882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10810882 Reactome R-CEL-8943778 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8943778.1 Reactome Database ID Release 82 10810884 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10810884 Reactome R-CEL-8943781 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8943781.1 Reactome Database ID Release 82 10810886 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10810886 Reactome R-CEL-8943780 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8943780.1 SALL4 recruits the transcriptional repressor complex NuRD, containing histone deacetylases HDAC1 and HDAC2, to the PTEN gene promoter (Lu et al 2009, Gao et al. 2013). SALL4 may also recruit DNA methyltransferases (DNMTs) to the PTEN promoter (Yang et al. 2012). 22128185 Pubmed 2012 Stem cell gene SALL4 suppresses transcription through recruitment of DNA methyltransferases Yang, Jianchang Corsello, Tyler R Ma, Yupo J. Biol. Chem. 287:1996-2005 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 23287862 Pubmed 2013 Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex Gao, Chong Dimitrov, Todor Yong, Kol Jia Tatetsu, Hiro Jeong, Ha-Won Luo, Hongbo R Bradner, James E Tenen, Daniel G Chai, Li Blood 121:1413-21 inferred by electronic annotation IEA GO IEA MECOM (EVI1) recruits polycomb repressor complexes (PRCs) to the PTEN gene promoter MECOM (EVI1) recruits polycomb repressor complexes (PRCs) to the PTEN gene promoter This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10810906 1 MECOM:PTEN gene [nucleoplasm] MECOM:PTEN gene Reactome DB_ID: 10810839 1 Converted from EntitySet in Reactome Reactome DB_ID: 10810896 1 Homologues of MECOM [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MECOM [nucleoplasm] che-1 [nucleoplasm] egl-43 [nucleoplasm] MECOM [nucleoplasm] UniProt Q4TT89 UniProt Q966L8 UniProt Q22024 UniProt Q9U235 Reactome Database ID Release 82 10810906 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10810906 Reactome R-CEL-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-CEL-8943810.1 Converted from EntitySet in Reactome Reactome DB_ID: 10810904 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: 10810910 1 MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene Reactome DB_ID: 10810839 1 Reactome DB_ID: 10810908 1 MECOM:(PRC1.4,PRC2 (EZH2) core) [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core) Converted from EntitySet in Reactome Reactome DB_ID: 10810896 1 Converted from EntitySet in Reactome Reactome DB_ID: 10810904 1 Reactome Database ID Release 82 10810908 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10810908 Reactome R-CEL-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-CEL-8943820.1 Reactome Database ID Release 82 10810910 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10810910 Reactome R-CEL-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-CEL-8943821.1 Reactome Database ID Release 82 10810912 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10810912 Reactome R-CEL-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-CEL-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 2.7.11.1 mTORC1 phosphorylates MAF1 mTORC1 phosphorylates MAF1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 3 Reactome DB_ID: 10811064 1 UniProt:Q9TZN2 mafr-1 UniProt Q9TZN2 1 EQUAL 256 EQUAL Reactome DB_ID: 10811069 1 O-phospho-L-serine at 60 (in Homo sapiens) 60 EQUAL O-phospho-L-serine at 68 (in Homo sapiens) 68 EQUAL O-phospho-L-serine at 75 (in Homo sapiens) 75 EQUAL 1 EQUAL 256 EQUAL Reactome DB_ID: 29370 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10751855 lysosomal membrane GO 0005765 Active mTORC1 complex [lysosomal membrane] Active mTORC1 complex Reactome DB_ID: 10751774 1 RHEB:GTP [lysosomal membrane] RHEB:GTP Reactome DB_ID: 29438 1 Reactome DB_ID: 10751770 1 UniProt:P34443 UniProt P34443 1 EQUAL 181 EQUAL Reactome Database ID Release 82 10751774 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751774 Reactome R-CEL-165189 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-165189.1 Reactome DB_ID: 10751853 1 mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 [lysosomal membrane] mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Reactome DB_ID: 10751793 1 mTORC1 [cytosol] mTORC1 Reactome DB_ID: 10751791 1 UniProt:Q68TI8 daf-15 UniProt Q68TI8 1 EQUAL 1335 EQUAL Reactome DB_ID: 10751786 1 1 EQUAL 2549 EQUAL Reactome DB_ID: 10751781 1 1 EQUAL 326 EQUAL Reactome Database ID Release 82 10751793 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751793 Reactome R-CEL-377400 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-377400.1 Reactome DB_ID: 10751851 1 Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 [lysosomal membrane] Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Reactome DB_ID: 10751849 1 Ragulator:RagA,B:GTP:RagC,D:GDP [lysosomal membrane] Ragulator:RagA,B:GTP:RagC,D:GDP Reactome DB_ID: 10751847 1 RagA,B:GTP:RagC,D:GDP [cytosol] RagA,B:GTP:RagC,D:GDP Converted from EntitySet in Reactome Reactome DB_ID: 10751832 1 RRAGA, RRAGB:GTP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 10751845 1 RRAGC,RRAGD:GDP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 10751847 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751847 Reactome R-CEL-5653945 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5653945.1 Reactome DB_ID: 10751819 1 Ragulator [lysosomal membrane] Ragulator Reactome DB_ID: 10751810 1 UniProt:Q8WQG5 lmtr-3 UniProt Q8WQG5 1 EQUAL 124 EQUAL Reactome DB_ID: 10751817 1 UniProt:O17268 lmtr-5 UniProt O17268 1 EQUAL 91 EQUAL Reactome DB_ID: 10751812 1 Ghost homologue of LAMTOR4 [lysosomal membrane] Ghost homologue of LAMTOR4 Reactome DB_ID: 10751800 1 Ghost homologue of LAMTOR1 [lysosomal membrane] Ghost homologue of LAMTOR1 Reactome DB_ID: 10751805 1 UniProt:Q9N2U6 lmtr-2 UniProt Q9N2U6 1 EQUAL 125 EQUAL Reactome Database ID Release 82 10751819 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751819 Reactome R-CEL-5653921 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5653921.1 Reactome Database ID Release 82 10751849 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751849 Reactome R-CEL-5653979 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5653979.1 Reactome DB_ID: 10751798 1 UniProt:Q19425 UniProt Q19425 1 EQUAL 561 EQUAL Reactome Database ID Release 82 10751851 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751851 Reactome R-CEL-8952725 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8952725.1 Reactome Database ID Release 82 10751853 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751853 Reactome R-CEL-5653972 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5653972.1 Reactome Database ID Release 82 10751855 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10751855 Reactome R-CEL-165678 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-165678.1 Reactome Database ID Release 82 10811070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10811070 Reactome Database ID Release 82 10811072 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10811072 Reactome R-CEL-8944454 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8944454.1 Activated mTORC1 complex phosphorylates the transcription factor MAF1 on serine residues S60, S68 and S75 (Shor et al. 2010, Michels et al. 2010). mTORC1-mediated phosphorylation of MAF1 inhibits translocation of MAF1 to the nucleus (Shor et al. 2010). 20233713 Pubmed 2010 Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells Shor, Boris Wu, Jiang Shakey, Quazi Toral-Barza, Lourdes Shi, Celine Follettie, Max Yu, Ker J. Biol. Chem. 285:15380-92 20516213 Pubmed 2010 mTORC1 directly phosphorylates and regulates human MAF1 Michels, Annemieke A Robitaille, Aaron M Buczynski-Ruchonnet, Diane Hodroj, Wassim Reina, Jaime H Hall, Michael N Hernandez, Nouria Mol. Cell. Biol. 30:3749-57 inferred by electronic annotation IEA GO IEA MAF1 translocates to the nucleus MAF1 translocates to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10811064 1 1 EQUAL 256 EQUAL Reactome DB_ID: 10811062 1 1 EQUAL 256 EQUAL Reactome Database ID Release 82 10811074 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10811074 Reactome R-CEL-8944457 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8944457.1 Phosphorylation of MAF1 by the activated mTORC1 complex inhibits translocation of MAF1 to the nucleus, and hence its transcriptional activity, but the mechanism has not been elucidated (Shor et al. 2010). inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 10811075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10811075 Reactome DB_ID: 10751855 Reactome Database ID Release 82 10818837 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10818837 Reactome R-CEL-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-CEL-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 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 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> Reactome Database ID Release 82 10818843 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10818843 Reactome R-CEL-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-CEL-8948751.1 PTEN protein stability is regulated by ubiquitin ligases, such as NEDD4, WWP2, STUB1 (CHIP), XIAP, MKRN1 and RNF146, which polyubiquitinate PTEN in response to different stimuli and thus target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Maddika et al. 2011, Ahmed et al. 2012, Lee et al. 2015, Li et al. 2015). Several ubiquitin proteases, such as USP13 and OTUD3, can remove polyubiquitin chains from PTEN and rescue it from degradation (Zhang et al. 2013, Yuan et al. 2015). TRIM27 (RFP) is an E3 ubiquitin ligase that polyubiquitinates PTEN on multiple lysines in the C2 domain of PTEN using K27 linkage between ubiquitin molecules. TRIM27 mediated ubiquitination inhibits PTEN lipid phosphatase activity, but does not affect PTEN protein localization or stability (Lee et al. 2013).<br>PTEN phosphorylation by the tyrosine kinase FRK (RAK) inhibits NEDD4 mediated polyubiquitination and subsequent degradation of PTEN, thus increasing PTEN half life. FRK mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase 2 (CK2) mediated phosphorylation of the C-terminus of PTEN on multiple serine and threonine residues increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).<br>PREX2, a RAC1 guanine nucleotide exchange factor (GEF) can binds to PTEN and inhibit its catalytic activity (Fine et al. 2009). 19729658 Pubmed 2009 Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a Fine, Barry Hodakoski, Cindy Koujak, Susan Su, Tao Saal, Lao H Maurer, Matthew Hopkins, Benjamin Keniry, Megan Sulis, ML Mense, Sarah Hibshoosh, Hanina Parsons, R Science 325:1261-5 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 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 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 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 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 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 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 Reactome Database ID Release 82 10818839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10818839 Reactome R-CEL-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-CEL-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 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 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 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 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 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 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 18757404 Pubmed 2008 PTEN acetylation modulates its interaction with PDZ domain Ikenoue, T Inoki, Ken Zhao, B Guan, KL Cancer Res. 68:6908-12 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 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 10816995 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10816995 Reactome R-CEL-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-CEL-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