BioPAX pathway converted from "PIP3 activates AKT signaling" in the Reactome database. PIP3 activates AKT signaling PIP3 activates AKT signaling PI3K/AKT Signaling 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. Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 RAC1,RAC2,RHOG activate PI3K RAC1,RAC2,RHOG activate PI3K 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. Edited: Jupe, S, 2009-09-09 Converted from EntitySet in Reactome Reactome DB_ID: 9615275 1 plasma membrane GO 0005886 RAC1:GTP,RAC2:GTP,RHOG:GTP [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome http://www.reactome.org Reactome DB_ID: 198379 1 cytosol GO 0005829 PI3K alpha [cytosol] PI3K alpha Reactome DB_ID: 74787 1 UniProt:P42336 PIK3CA PIK3CA PIK3CA FUNCTION Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396, PubMed:23936502, PubMed:28676499). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396, PubMed:28676499). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. In addition to its lipid kinase activity, it displays a serine-protein kinase activity that results in the autophosphorylation of the p85alpha regulatory subunit as well as phosphorylation of other proteins such as 4EBP1, H-Ras, the IL-3 beta c receptor and possibly others (PubMed:23936502, PubMed:28676499). Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity).PATHWAY Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.SUBUNIT Heterodimer of a catalytic subunit PIK3CA and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3) (PubMed:26593112). Interacts with IRS1 in nuclear extracts (By similarity). Interacts with RUFY3 (By similarity). Interacts with RASD2 (By similarity). Interacts with APPL1. Interacts with HRAS and KRAS (By similarity). Interaction with HRAS/KRAS is required for PI3K pathway signaling and cell proliferation stimulated by EGF and FGF2 (By similarity). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467).DOMAIN The PI3K-ABD domain and the PI3K-RBD domain interact with the PI3K/PI4K kinase domain. The C2 PI3K-type domain may facilitate the recruitment to the plasma membrane. The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1, and the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1.DISEASE PIK3CA mutations are involved in various type of cancer. Most of the cancer-associated mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS/KRAS. Interaction with HRAS/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis.MISCELLANEOUS The avian sarcoma virus 16 genome encodes an oncogene derived from PIK3CA.SIMILARITY Belongs to the PI3/PI4-kinase family. Homo sapiens NCBI Taxonomy 9606 UniProt P42336 Chain Coordinates 1 EQUAL 1068 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 391342 1 PI3K-regulatory subunits [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PIK3R1 [cytosol] UniProt P27986 Reactome Database ID Release 82 198379 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198379 Reactome R-HSA-198379 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198379.1 Reactome DB_ID: 114540 1 RAC1:GTP,RAC2:GTP,RHOG:GTP:PI3K alpha [plasma membrane] RAC1:GTP,RAC2:GTP,RHOG:GTP:PI3K alpha Converted from EntitySet in Reactome Reactome DB_ID: 9615275 1 Reactome DB_ID: 198379 1 Reactome Database ID Release 82 114540 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114540 Reactome R-HSA-114540 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114540.3 Reactome Database ID Release 82 114542 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=114542 Reactome R-HSA-114542 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-114542.3 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 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 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 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 2.7.1.153 PI3K phosphorylates PIP2 to PIP3 PI3K phosphorylates PIP2 to PIP3 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). Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Reviewed: Porteu, Françoise, 2016-02-08 Edited: Matthews, L, 2012-08-03 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: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 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 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2316432 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 2316433 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316433 Reactome Database ID Release 82 2316434 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316434 Reactome R-HSA-2316434 7 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316434.7 9739761 Pubmed 1998 Signal transduction via platelet-derived growth factor receptors Heldin, Carl-Henrik Ostman, A Rönnstrand, Lars Biochim Biophys Acta 1378:F79-113 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 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 2466336 Pubmed 1989 Role of phosphatidylinositol kinase in PDGF receptor signal transduction Coughlin, SR Escobedo, JA Williams, LT Science 243:1191-4 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 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 15863030 Pubmed 2005 Cellular signaling by fibroblast growth factor receptors Eswarakumar, VP Lax, I Schlessinger, J Cytokine Growth Factor Rev 16:139-49 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 15526160 Pubmed 2004 Signal transduction via the stem cell factor receptor/c-Kit Rönnstrand, Lars Cell Mol Life Sci 61:2535-48 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 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 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 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 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 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 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 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 12660731 Pubmed 2003 The role of PI3K in immune cells Koyasu, S Nat Immunol 4:313-9 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 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 GO 0051897 GO biological process ACTIVATION Reactome Database ID Release 82 8981988 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8981988 Reactome R-HSA-8981988 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8981988.1 Reactome DB_ID: 8981951 IL33:IL1RL1:IL1RAP-1:MYD88 dimer:IRAK1,IRAK4,TRAF6 [plasma membrane] IL33:IL1RL1:IL1RAP-1:MYD88 dimer:IRAK1,IRAK4,TRAF6 Reactome DB_ID: 166081 1 UniProt:Q9NWZ3 IRAK4 IRAK4 IRAK4 FUNCTION Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.SUBUNIT Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome (PubMed:16951688, PubMed:24316379). Once phosphorylated, IRAK4 dissociates from the receptor complex and then associates with the TNF receptor-associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate complex is required for subsequent NF-kappa-B activation (PubMed:11960013, PubMed:12496252, PubMed:16951688). Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression (PubMed:16951688). Interacts with IL1RL1 (PubMed:16286016). Interacts (when phosphorylated) with IRAK1 (PubMed:33238146). May interact (when phosphorylated) with IRAK3 (PubMed:33238146).PTM Phosphorylated.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. UniProt Q9NWZ3 1 EQUAL 460 EQUAL Reactome DB_ID: 446639 1 UniProt:P51617 IRAK1 IRAK1 IRAK IRAK1 FUNCTION Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.SUBUNIT Homodimer (By similarity). Forms a complex with TRAF6, PELI1, IRAK4 and MYD88 (PubMed:16951688). Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression (PubMed:16951688). The TRAF6-PELI1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation (PubMed:16951688). Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex (PubMed:9430229). Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation (PubMed:10854325). Interacts with IL1RL1 (PubMed:16286016). Interacts with PELI1 and TRAF6 (PubMed:12496252). Interacts (when polyubiquitinated) with IKBKG/NEMO (PubMed:18347055). Interacts with RSAD2/viperin (By similarity). Interacts with IRAK1BP1 (By similarity). Interacts with PELI2 (By similarity). Interacts with ZC3H12A; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (By similarity). Interacts with IRAK4 (PubMed:11960013). Interacts with PELI3 (PubMed:12874243). Interacts with INAVA; the interaction takes place upon PRR stimulation (PubMed:28436939). Interacts (via C-terminus) with NFATC4 (via N-terminus) (PubMed:18691762).SUBUNIT (Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation.SUBUNIT (Microbial infection) Interacts with alphaviruses SINV, CHIKV, RRV, VEEV and EEEV capsid proteins; the interactions lead to inhibition of IRAK1-dependent signaling.TISSUE SPECIFICITY Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2.DOMAIN The ProST region is composed of many proline and serine residues (more than 20 of each) and some threonines. This region is the site of IRAK-1 hyperphosphorylation.PTM Following recruitment on the activated receptor complex, phosphorylated on Thr-209, probably by IRAK4, resulting in a conformational change of the kinase domain, allowing further phosphorylations to take place. Thr-387 phosphorylation in the activation loop is required to achieve full enzymatic activity.PTM Polyubiquitinated by TRAF6 after cell stimulation with IL-1-beta by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin chains linked through 'Lys-63'. Ubiquitination promotes interaction with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. UniProt P51617 1 EQUAL 712 EQUAL Reactome DB_ID: 8981947 1 IL33:IL1RL1:IL1RAP-1:MYD88 dimer [plasma membrane] IL33:IL1RL1:IL1RAP-1:MYD88 dimer Reactome DB_ID: 193932 1 MYD88 dimer [cytosol] MYD88 dimer 2xMYD88 MYD88 homodimer Reactome DB_ID: 166059 2 UniProt:Q99836 MYD88 MYD88 MYD88 FUNCTION Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response (PubMed:15361868, PubMed:18292575, PubMed:33718825). Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:15361868, PubMed:24316379, PubMed:19506249). Increases IL-8 transcription (PubMed:9013863). Involved in IL-18-mediated signaling pathway. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. Upon TLR8 activation by GU-rich single-stranded RNA (GU-rich RNA) derived from viruses such as SARS-CoV-2, SARS-CoV and HIV-1, induces IL1B release through NLRP3 inflammasome activation (PubMed:33718825). MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine (By similarity).SUBUNIT Homodimer. Also forms heterodimers with TIRAP. Binds to TLR2, TLR4, TLR5, IRAK1, IRAK2 and IRAK4 via their respective TIR domains. Interacts with IL18R1. Interacts with BMX, IL1RL1, IKBKE and IRF7. Interacts with LRRFIP1 and LRRFIP2; this interaction positively regulates Toll-like receptor (TLR) signaling in response to agonist. Interacts with FLII. LRRFIP1 and LRRFIP2 compete with FLII for MYD88-binding. Interacts with IRF1. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and TRAF6; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. May interact with PIK3AP1. Interacts (via TIR domain) with DHX9 (via H2A and OB-fold regions); this interaction is direct (PubMed:20696886). Interacts with OTUD4 deubiquitinase; the interaction is direct (PubMed:29395066).SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC; suppressing Toll-like receptor (TLR)-mediated cytokine production.SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.faecalis protein TcpF; suppressing Toll-like receptor (TLR)-mediated cytokine production.TISSUE SPECIFICITY Ubiquitous.DOMAIN The intermediate domain (ID) is required for the phosphorylation and activation of IRAK.PTM Ubiquitinated; undergoes 'Lys-63'-linked polyubiquitination. OTUD4 specifically hydrolyzes 'Lys-63'-linked polyubiquitinated MYD88.DISEASE Defects in MYD88 are frequently found in many hematological malignancies, such as activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL), cutaneous diffuse large B cell lymphoma (CBCL) and primary central nervous system lymphoma (PCNSL). UniProt Q99836 1 EQUAL 296 EQUAL Reactome Database ID Release 82 193932 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=193932 Reactome R-HSA-193932 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-193932.3 Reactome DB_ID: 448571 1 IL33:IL1RL1:IL1RAP-1 [plasma membrane] IL33:IL1RL1:IL1RAP-1 Interleukin-1 receptor-like 1:interleukin-33 Reactome DB_ID: 448601 1 IL1RL1:IL33 [plasma membrane] IL1RL1:IL33 Interleukin-33 receptor Reactome DB_ID: 197594 1 UniProt:Q01638 IL1RL1 IL1RL1 ST2 IL1RL1 DER4 T1 FUNCTION Receptor for interleukin-33 (IL-33); signaling requires association of the coreceptor IL1RAP. Its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8. Possibly involved in helper T-cell function.SUBUNIT Interacts with MYD88, IRAK1, IRAK4, and TRAF6. Bound to its ligand IL-33, interacts with IL1RAP to form the minimal interleukin-33 signaling complex with a 1:1:1 stoichiometry. Interacts with KIT (bound to KITLG/SCF). A mast cell-specific KITLG/SCF-induced interleukin-33 signaling complex contains IL1RL1, IL1RAP, KIT and MYD88. Interacts with TMED1 (PubMed:23319592).TISSUE SPECIFICITY Highly expressed in kidney, lung, placenta, stomach, skeletal muscle, colon and small intestine. Isoform A is prevalently expressed in the lung, testis, placenta, stomach and colon. Isoform B is more abundant in the brain, kidney and the liver. Isoform C is not detected in brain, heart, liver, kidney and skeletal muscle. Expressed on T-cells in fibrotic liver; at protein level. Overexpressed in fibrotic and cirrhotic liver.DOMAIN The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity.SIMILARITY Belongs to the interleukin-1 receptor family. UniProt Q01638 19 EQUAL 556 EQUAL Reactome DB_ID: 448567 1 extracellular region GO 0005576 UniProt:O95760 IL33 IL33 IL1F11 IL33 C9orf26 NFHEV FUNCTION Cytokine that binds to and signals through the IL1RL1/ST2 receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells (PubMed:16286016). Involved in the maturation of Th2 cells inducing the secretion of T-helper type 2-associated cytokines. Also involved in activation of mast cells, basophils, eosinophils and natural killer cells. Acts as a chemoattractant for Th2 cells, and may function as an 'alarmin', that amplifies immune responses during tissue injury (PubMed:17853410, PubMed:18836528).FUNCTION In quiescent endothelia the uncleaved form is constitutively and abundantly expressed, and acts as a chromatin-associated nuclear factor with transcriptional repressor properties, it may sequester nuclear NF-kappaB/RELA, lowering expression of its targets (PubMed:21734074). This form is rapidely lost upon angiogenic or pro-inflammatory activation (PubMed:18787100).SUBUNIT Forms a 1:1:1 heterotrimeric complex with its primary high-affinity receptor IL1RL1 and the coreceptor IL1RAP. Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion (PubMed:32272059).SUBUNIT (Microbial infection) Interacts (in reduced form) with H.polygyrus ARI.TISSUE SPECIFICITY Expressed at high level in high endothelial venules found in tonsils, Peyer patches and mesenteric lymph nodes. Almost undetectable in placenta.INDUCTION By infection with the parasite H.polygyrus.DOMAIN The homeodomain-like HTH domain mediates nuclear localization and heterochromatin association.PTM The full-length protein can be released from cells and is able to signal via the IL1RL1/ST2 receptor. However, proteolytic processing by CSTG/cathepsin G and ELANE/neutrophil elastase produces C-terminal peptides that are more active than the unprocessed full length protein. May also be proteolytically processed by calpains (PubMed:19596270). Proteolytic cleavage mediated by apoptotic caspases including CASP3 and CASP7 results in IL33 inactivation (PubMed:19559631). In vitro proteolytic cleavage by CASP1 was reported (PubMed:16286016) but could not be confirmed in vivo (PubMed:19465481) suggesting that IL33 is probably not a direct substrate for that caspase.SIMILARITY Belongs to the IL-1 family. Highly divergent. UniProt O95760 1 EQUAL 270 EQUAL Reactome Database ID Release 82 448601 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=448601 Reactome R-HSA-448601 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-448601.1 Reactome DB_ID: 445745 1 UniProt:Q9NPH3-1 IL1RAP IL1RAP IL1R3 IL1RAP C3orf13 FUNCTION Coreceptor for IL1RL2 in the IL-36 signaling system (By similarity). Coreceptor with IL1R1 in the IL-1 signaling system. Associates with IL1R1 bound to IL1B to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Recruits TOLLIP to the signaling complex. Does not bind to interleukin-1 alone; binding of IL1RN to IL1R1, prevents its association with IL1R1 to form a signaling complex. The cellular response is modulated through a non-signaling association with the membrane IL1R2 decoy receptor. Coreceptor for IL1RL1 in the IL-33 signaling system. Can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to PTPRD (By similarity). May play a role in IL1B-mediated costimulation of IFNG production from T-helper 1 (Th1) cells (Probable).SUBUNIT The interleukin-36 receptor complex is a heterodimer of IL1RL2 and IL1RAP; the association is inhibited by IL36RN (By similarity). The interleukin-1 receptor complex is a heterodimer of IL1R1 and IL1RAP. Associates with IL1R2 to form a non-signaling interleukin-1 receptor complex. Isoform 4 interacts with IL1R1 in an interleukin-1-dependent manner. Interacts with IL-33-bound IL1RL1 to form the minimal interleukin-33 signaling complex with a 1:1:1 stoichiometry. Interacts with KIT (independently of stimulation with KITLG/SCF). A mast cell-specific KITLG/SCF-induced interleukin-33 signaling complex contains IL1RL1, IL1RAP, KIT and MYD88 (By similarity). Interacts (via the first immunoglobilin domain) with PTPRD (via the third immunoglobilin domain); induces pre- and postsynaptic differentiation of neurons (By similarity).TISSUE SPECIFICITY Detected in liver, skin, placenta, thymus and lung. Isoform 4 is predominantly expressed in brain. Overexpressed on candidate chronic myeloid leukemia (CML) stem cells, hematopoietic stem cells and mononuclear cells of patients with acute myeloid leukemia (AML). Overexpressed in patients with chronic obstructive pulmonary disease (COPD). Expressed in T-helper 1 (Th1) and T-helper 2 (Th2) cell subsets (PubMed:10653850).INDUCTION Isoform 1 is down-regulated by phorbol ester treatment. Isoform 2 is induced by phorbol ester treatment.DOMAIN The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity.SIMILARITY Belongs to the interleukin-1 receptor family. UniProt Q9NPH3-1 21 EQUAL 570 EQUAL Reactome Database ID Release 82 448571 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=448571 Reactome R-HSA-448571 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-448571.1 Reactome Database ID Release 82 8981947 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8981947 Reactome R-HSA-8981947 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8981947.2 Reactome DB_ID: 166366 1 UniProt:Q9Y4K3 TRAF6 TRAF6 TRAF6 RNF85 FUNCTION E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2 (PubMed:11057907, PubMed:18347055, PubMed:19713527, PubMed:19465916). Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation (PubMed:19675569). Leads to the activation of NF-kappa-B and JUN (PubMed:16378096, PubMed:17135271). Seems to also play a role in dendritic cells (DCs) maturation and/or activation (By similarity). Represses c-Myb-mediated transactivation, in B-lymphocytes (PubMed:18093978, PubMed:18758450). Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor (PubMed:8837778, PubMed:19825828, PubMed:12140561). Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation (By similarity). Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer. Homooligomer. N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK2, IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and PELI3. Binds UBE2V1. Interacts with TAX1BP1. Interacts with ZNF675. Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal). Interacts with RBCK1. Interacts with LIMD1 (via LIM domains) (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with IFIT3 (via N-terminus). Interacts with TICAM2. Interacts with CARD14. Interacts with CD40 and MAP3K8; the interaction is required for ERK activation (By similarity). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (PubMed:25861989). Interacts with WDFY3 (By similarity). Interacts with TRIM13 (PubMed:28087809). Interacts with GPS2 (By similarity). Interacts (via C-terminus) with SASH1 (PubMed:23776175). Interacts with LRRC19 (PubMed:25026888). Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70 (PubMed:20628368). Interacts with AMBRA1; interaction is required to mediate 'Lys-63'-linked ubiquitination of ULK1 (PubMed:23524951).TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.PTM Sumoylated on Lys-124, Lys-142 and Lys-453 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (PubMed:19825828). Polyubiquitinated on Lys-124; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappaB signaling upon DNA damage (PubMed:25861989). LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. UniProt Q9Y4K3 1 EQUAL 522 EQUAL Reactome Database ID Release 82 8981951 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8981951 Reactome R-HSA-8981951 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8981951.2 PIP3 recruits AKT to the membrane PIP3 recruits AKT to the membrane 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. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Converted from EntitySet in Reactome Reactome DB_ID: 202088 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] UniProt P31749 Reactome DB_ID: 179838 1 Reactome DB_ID: 2317329 1 AKT:PIP3 [plasma membrane] AKT:PIP3 Reactome DB_ID: 179838 1 Converted from EntitySet in Reactome Reactome DB_ID: 202052 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] Reactome Database ID Release 82 2317329 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2317329 Reactome R-HSA-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-HSA-2317329.1 Reactome Database ID Release 82 2317332 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2317332 Reactome R-HSA-2317332 6 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2317332.6 2008 The role of Akt3 in Platelet Activation O'Brien, K Stojanovic, A Hay, N Du, X Arteriosclerosis, Thrombosis, and Vascular Biology 28:e162 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 GO 0032148 GO biological process PIP3 recruits PDPK1 to the membrane PIP3 recruits PDPK1 to the membrane 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). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 179838 1 Reactome DB_ID: 202210 1 UniProt:O15530 PDPK1 PDPK1 PDPK1 PDK1 FUNCTION Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive.ACTIVITY REGULATION Homodimerization regulates its activity by maintaining the kinase in an autoinhibitory conformation. NPRL2 down-regulates its activity by interfering with tyrosine phosphorylation at the Tyr-9, Tyr-373 and Tyr-376 residues. The 14-3-3 protein YWHAQ acts as a negative regulator by association with the residues surrounding the Ser-241 residue. STRAP positively regulates its activity by enhancing its autophosphorylation and by stimulating its dissociation from YWHAQ. SMAD2, SMAD3, SMAD4 and SMAD7 also positively regulate its activity by stimulating its dissociation from YWHAQ. Activated by phosphorylation on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin.SUBUNIT Homodimer in its autoinhibited state. Active as monomer. Interacts with NPRL2, PPARG, PAK1, PTK2B, GRB14, PKN1 (via C-terminus), STRAP and IKKB. The Tyr-9 phosphorylated form interacts with SRC, RASA1 and CRK (via their SH2 domains). Interacts with SGK3 in a phosphorylation-dependent manner. The tyrosine-phosphorylated form interacts with PTPN6. The Ser-241 phosphorylated form interacts with YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH domain) with SMAD3, SMAD4 and SMAD7. Interacts with PKN2; the interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-dependent kinase activity toward 'Ser-473' of AKT1 but also activates its kinase activity toward PRKCD and PRKCZ.TISSUE SPECIFICITY Appears to be expressed ubiquitously. The Tyr-9 phosphorylated form is markedly increased in diseased tissue compared with normal tissue from lung, liver, colon and breast.INDUCTION Stimulated by insulin, and the oxidants hydrogen peroxide and peroxovanadate.DOMAIN The PH domain plays a pivotal role in the localization and nuclear import of PDPK1 and is also essential for its homodimerization.DOMAIN The PIF-pocket is a small lobe in the catalytic domain required by the enzyme for the binding to the hydrophobic motif of its substrates. It is an allosteric regulatory site that can accommodate small compounds acting as allosteric inhibitors.PTM Phosphorylation on Ser-241 in the activation loop is required for full activity. PDPK1 itself can autophosphorylate Ser-241, leading to its own activation. Autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2 (By similarity). Tyr-9 phosphorylation is critical for stabilization of both PDPK1 and the PDPK1/SRC complex via HSP90-mediated protection of PDPK1 degradation. Angiotensin II stimulates the tyrosine phosphorylation of PDPK1 in vascular smooth muscle in a calcium- and SRC-dependent manner. Phosphorylated on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin. Palmitate negatively regulates autophosphorylation at Ser-241 and palmitate-induced phosphorylation at Ser-529 and Ser-501 by PKC/PRKCQ negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylation at Thr-354 by MELK partially inhibits kinase activity, the inhibition is cooperatively enhanced by phosphorylation at Ser-394 and Ser-398 by MAP3K5.PTM Autophosphorylated; autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2.PTM Monoubiquitinated in the kinase domain, deubiquitinated by USP4.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PDPK1 subfamily. UniProt O15530 1 EQUAL 556 EQUAL Reactome DB_ID: 377179 1 PDPK1:PIP3 [plasma membrane] PDPK1:PIP3 PDK1:PIP3 Reactome DB_ID: 61459 1 1 EQUAL 556 EQUAL Reactome DB_ID: 179838 1 Reactome Database ID Release 82 377179 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377179 Reactome R-HSA-377179 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377179.1 Reactome Database ID Release 82 2316429 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2316429 Reactome R-HSA-2316429 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2316429.3 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 2.7.11.1 TORC2 (mTOR) phosphorylates AKT at S473 TORC2 (mTOR) phosphorylates AKT at S473 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). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 2317329 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 2317310 1 p-S-AKT:PIP3 [plasma membrane] p-S-AKT:PIP3 Converted from EntitySet in Reactome Reactome DB_ID: 2317317 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 p-S473-AKT1 [plasma membrane] Reactome DB_ID: 179838 1 Reactome Database ID Release 82 2317310 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2317310 Reactome R-HSA-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-HSA-2317310.1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 198626 TORC2 complex [cytosol] TORC2 complex mTORC2 mTOR2 Reactome DB_ID: 165676 1 UniProt:Q9BVC4 MLST8 MLST8 GBL MLST8 LST8 FUNCTION Subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, LST8 interacts directly with MTOR and enhances its kinase activity. In nutrient-poor conditions, stabilizes the MTOR-RPTOR interaction and favors RPTOR-mediated inhibition of MTOR activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Interacts directly with MTOR and RPTOR. Interacts with RHEB. Interacts with MEAK7 (PubMed:29750193). Interacts with SIK3 (PubMed:30232230).TISSUE SPECIFICITY Broadly expressed, with highest levels in skeletal muscle, heart and kidney.SIMILARITY Belongs to the WD repeat LST8 family. UniProt Q9BVC4 1 EQUAL 326 EQUAL Reactome DB_ID: 165662 1 UniProt:P42345 MTOR MTOR FRAP1 RAFT1 FRAP2 FRAP RAPT1 MTOR FUNCTION Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18925875, PubMed:18497260, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (By similarity). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4 (PubMed:12150925, PubMed:12087098, PubMed:18925875). This also includes mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3: in the presence of nutrients, mediates phosphorylation of TFEB and TFE3, promoting their cytosolic retention and inactivation (PubMed:22576015, PubMed:22343943, PubMed:22692423). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex (PubMed:23429704, PubMed:23429703). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (By similarity). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). mTORC1 also negatively regulates autophagy through phosphorylation of ULK1 (By similarity). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (PubMed:20537536). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (PubMed:30704899). Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA (PubMed:23524951, PubMed:25438055). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (PubMed:21659604). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (PubMed:12231510). As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton (PubMed:15268862, PubMed:15467718). Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1 (PubMed:15718470). mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B (PubMed:15268862). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:18925875). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity). Phosphorylates SQSTM1, promoting interaction between SQSTM1 and KEAP1 and subsequent inactivation of the BCR(KEAP1) complex (By similarity).ACTIVITY REGULATION Activation of mTORC1 by growth factors such as insulin involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase a potent activator of the protein kinase activity of mTORC1. Insulin-stimulated and amino acid-dependent phosphorylation at Ser-1261 promotes autophosphorylation and the activation of mTORC1. Activation by amino acids requires relocalization of the mTORC1 complex to lysosomes that is mediated by the Ragulator complex, SLC38A9, and the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD (PubMed:18497260, PubMed:20381137, PubMed:25561175, PubMed:25567906). On the other hand, low cellular energy levels can inhibit mTORC1 through activation of PRKAA1 while hypoxia inhibits mTORC1 through a REDD1-dependent mechanism which may also require PRKAA1. The kinase activity of MTOR within the mTORC1 complex is positively regulated by MLST8 and negatively regulated by DEPTOR and AKT1S1. MTOR phosphorylates RPTOR which in turn inhibits mTORC1. MTOR is the target of the immunosuppressive and anti-cancer drug rapamycin which acts in complex with FKBP1A/FKBP12, and specifically inhibits its kinase activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. It may be regulated by RHEB but in an indirect manner through the PI3K signaling pathway.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. The mTORC1 complex is a 1 Md obligate dimer of two stoichiometric heterotetramers with overall dimensions of 290 A x 210 A x 135 A. It has a rhomboid shape and a central cavity, the dimeric interfaces are formed by interlocking interactions between the two MTOR and the two RPTOR subunits. The MLST8 subunit forms distal foot-like protuberances, and contacts only one MTOR within the complex, while the small PRAS40 localizes to the midsection of the central core, in close proximity to RPTOR. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Interacts with PLPP7 and PML. Interacts with PRR5 and RICTOR; the interaction is direct within the mTORC2 complex and interaction with RICTOR is enhanced by deubiquitination of RICTOR by USP9X (PubMed:33378666). Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). Interacts with UBQLN1. Interacts with TTI1 and TELO2. Interacts with CLIP1; phosphorylates and regulates CLIP1. Interacts with NBN. Interacts with HTR6 (PubMed:23027611). Interacts with BRAT1. Interacts with MEAK7 (via C-terminal domain); the interaction increases upon nutrient stimulation (PubMed:29750193). Interacts with TM4SF5; the interaction is positively regulated by arginine and is negatively regulated by leucine (PubMed:30956113). Interacts with GPR137B (PubMed:31036939). Interacts with NCKAP1L (PubMed:32647003). Interacts with TPCN1 and TPCN2; the interaction is required for TPCN1 and TPCN2 sensitivity to ATP (PubMed:23394946). Interacts with ATP6V1A and with CRYAB, forming a ternary complex (By similarity).TISSUE SPECIFICITY Expressed in numerous tissues, with highest levels in testis.DOMAIN The kinase domain (PI3K/PI4K) is intrinsically active but has a highly restricted catalytic center.DOMAIN The FAT domain forms three discontinuous subdomains of alpha-helical TPR repeats plus a single subdomain of HEAT repeats. The four domains pack sequentially to form a C-shaped a-solenoid that clamps onto the kinase domain (PubMed:23636326).PTM Autophosphorylates when part of mTORC1 or mTORC2. Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes autophosphorylation. Phosphorylation in the kinase domain modulates the interactions of MTOR with RPTOR and PRAS40 and leads to increased intrinsic mTORC1 kinase activity. Phosphorylation at Thr-2173 in the ATP-binding region by AKT1 strongly reduces kinase activity.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt P42345 1 EQUAL 2549 EQUAL Reactome DB_ID: 3006620 1 UniProt:Q9BPZ7 MAPKAP1 MAPKAP1 MAPKAP1 MIP1 SIN1 FUNCTION Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Within mTORC2, MAPKAP1 is required for complex formation and mTORC2 kinase activity. MAPKAP1 inhibits MAP3K2 by preventing its dimerization and autophosphorylation. Inhibits HRAS and KRAS signaling. Enhances osmotic stress-induced phosphorylation of ATF2 and ATF2-mediated transcription. Involved in ciliogenesis, regulates cilia length through its interaction with CCDC28B independently of mTORC2 complex.SUBUNIT All isoforms except isoform 4 can be incorporated into the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (PubMed:16962653, PubMed:16919458, PubMed:33378666). Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Interacts with ATF2, MAP3K2 and MAPK8. Interacts with GTP-bound HRAS and KRAS. Interacts with IFNAR2 and SGK1. Isoform 2 interacts with NBN. Isoform 1 interacts with CCDC28B.TISSUE SPECIFICITY Ubiquitously expressed, with highest levels in heart and skeletal muscle.SIMILARITY Belongs to the SIN1 family. UniProt Q9BPZ7 2 EQUAL 522 EQUAL Reactome DB_ID: 6795323 1 UniProt:P85299 PRR5 PRR5 PRR5 PROTOR1 PP610 FUNCTION Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. PRR5 plays an important role in regulation of PDGFRB expression and in modulation of platelet-derived growth factor signaling. May act as a tumor suppressor in breast cancer.SUBUNIT Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Binds directly to MTOR and RICTOR within the TORC2 complex.TISSUE SPECIFICITY Most abundant in kidney and liver. Also highly expressed in brain, spleen, testis and placenta. Overexpressed in several colorectal tumors.SIMILARITY Belongs to the PROTOR family. UniProt P85299 1 EQUAL 388 EQUAL Reactome DB_ID: 198632 1 UniProt:Q6R327 RICTOR RICTOR KIAA1999 RICTOR FUNCTION Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Plays an essential role in embryonic growth and development.SUBUNIT Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (PubMed:15268862, PubMed:15467718, PubMed:17461779, PubMed:17599906). Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Binds directly to MTOR and PRR5 within the TORC2 complex; interaction with MTOR is enhanced by deubiquitination of RICTOR by USP9X (PubMed:15268862, PubMed:17461779, PubMed:17599906, PubMed:33378666). Interaction with MAPKAP1 is not enhanced by RICTOR deubiquitination by USP9X (PubMed:33378666). Interacts with CCDC28B (PubMed:23727834). Interacts with NBN (PubMed:23762398). Interacts with PRR5L (PubMed:17461779, PubMed:21964062). Interacts with SIK3 (PubMed:30232230). Interacts with NCKAP1L (PubMed:32647003). Interacts with kinases GSK3A and GSK3B; the interactions lead to phosphorylation of RICTOR at 'Thr-1695' which facilitates its FBXW7-mediated ubiquitination and subsequent degradation (PubMed:25897075). Interacts with FBXW7; the interaction is enhanced by GSK3-mediated phosphorylation of 'Thr-1695' and results in RICTOR ubiquitination and degradation (PubMed:25897075). Interacts with USP9X; the interaction results in deubiquitination of RICTOR and protection from proteasomal degradation, thus promoting mTORC2 complex assembly (PubMed:33378666).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein F17; this interaction dysregulates mTOR.PTM Phosphorylated by MTOR; when part of mTORC2 (PubMed:15467718). Phosphorylated at Thr-1135 by RPS6KB1; phosphorylation of RICTOR inhibits mTORC2 and AKT1 signaling (PubMed:19995915). Phosphorylated at Thr-1695 by GSK3A and GSK3B which facilitates RICTOR ubiquitination and subsequent degradation (PubMed:25897075).PTM Ubiquitinated by the SCF(FBXW7) complex, leading to its degradation by the proteasome (PubMed:25897075). Deubiquitinated by USP9X; deubiquitination stabilizes RICTOR and enhances its binding to MTOR, thus promoting mTORC2 complex assembly (PubMed:33378666).SIMILARITY Belongs to the RICTOR family. UniProt Q6R327 1 EQUAL 1708 EQUAL Reactome Database ID Release 82 198626 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198626 Reactome R-HSA-198626 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198626.2 GO 0004674 GO molecular function Reactome Database ID Release 82 198624 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198624 Reactome Database ID Release 82 198640 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198640 Reactome R-HSA-198640 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198640.4 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 15314020 Pubmed 2004 Upstream and downstream of mTOR Hay, N Sonenberg, Nahum Genes Dev 18:1926-45 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 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 INHIBITION Reactome Database ID Release 82 199457 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199457 Reactome R-HSA-199457 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199457.2 Reactome DB_ID: 199453 AKT:PIP3:THEM4/TRIB3 [plasma membrane] AKT:PIP3:THEM4/TRIB3 Reactome DB_ID: 2317329 1 Converted from EntitySet in Reactome Reactome DB_ID: 2400007 1 THEM4/TRIB3 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TRIB3 [plasma membrane] THEM4 [plasma membrane] UniProt Q96RU7 UniProt Q5T1C6 Reactome Database ID Release 82 199453 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199453 Reactome R-HSA-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-HSA-199453.1 AKT binds PDPK1 AKT binds PDPK1 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) Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 2317310 1 Reactome DB_ID: 377179 1 Reactome DB_ID: 2317313 1 p-S-AKT:PDPK1:PIP3 [plasma membrane] p-S-AKT:PDPK1:PIP3 Reactome DB_ID: 2317310 1 Reactome DB_ID: 377179 1 Reactome Database ID Release 82 2317313 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2317313 Reactome R-HSA-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-HSA-2317313.1 Reactome Database ID Release 82 2317314 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2317314 Reactome R-HSA-2317314 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2317314.3 2.7.11.1 PDPK1 phosphorylates AKT at T308 PDPK1 phosphorylates AKT at T308 Once AKT is localized at the plasma membrane, it is phosphorylated at two critical residues for its full activation. These residues are a threonine (T308 in AKT1) in the activation loop within the catalytic domain, and a serine (S473 in AKT1), in a hydrophobic motif (HM) within the carboxy terminal, non-catalytic region. PDPK1 (PDK1) is the activation loop kinase; this kinase can also directly phosphorylate p70S6K. The HM kinase, previously termed PDK2, has been identified as the mammalian TOR (Target Of Rapamycin; Sarbassov et al., 2005) but several other kinases are also able to phosphorylate AKT at S473. Phosphorylation of AKT at S473 by TORC2 complex is a prerequisite for PDPK1-mediated phosphorylation of AKT threonine T308 (Scheid et al. 2002, Sarabassov et al. 2005). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Reviewed: Messina, Francesco, 2022-02-18 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 2317313 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 377179 1 Converted from EntitySet in Reactome Reactome DB_ID: 202074 1 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 p-T308,S473-AKT1 [cytosol] Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2317313 Reactome Database ID Release 82 198343 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198343 Reactome Database ID Release 82 198270 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198270 Reactome R-HSA-198270 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198270.5 9736715 Pubmed 1998 Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase Delcommenne, M Tan, C Gray, V Rue, L Woodgett, J Dedhar, S Proc Natl Acad Sci U S A 95:11211-6 7637810 Pubmed 1995 Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction Burgering, BM Coffer, PJ Nature 376:599-602 34513728 Pubmed 2021 SARS-CoV-2 Membrane Glycoprotein M Triggers Apoptosis With the Assistance of Nucleocapsid Protein N in Cells Ren, Yujie Wang, An Fang, Yuan Shu, Ting Wu, Di Wang, Chong Huang, Muhan Min, Juan Jin, Liang Zhou, Wei Qiu, Yang Zhou, Xi Front Cell Infect Microbiol 11:706252 INHIBITION Reactome Database ID Release 82 9766197 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766197 Reactome DB_ID: 9755778 N:M:PDPK1 [plasma membrane] N:M:PDPK1 Reactome DB_ID: 9755780 1 UniProt:P0DTC5 M M M FUNCTION Component of the viral envelope that plays a central role in virus morphogenesis and assembly via its interactions with other viral proteins (By similarity). Regulates the localization of S protein at cis-Golgi, the place of virus budding (PubMed:33229438). May act by binding cytoplasmic c-terminus of S (PubMed:33229438).SUBUNIT Homomultimer. Interacts with envelope E protein in the budding compartment of the host cell, which is located between endoplasmic reticulum and the Golgi complex (By similarity). Forms a complex with S proteins (PubMed:33229438). Interacts with nucleocapsid N protein. This interaction probably participates in RNA packaging into the virus (By similarity). Interacts with the accessory proteins 3a and 7a (By similarity).PTM Glycosylated at N-terminus.POLYMORPHISM Variant Delta/B.1.617.2 belongs to a lineage first isolated in India (October 2020) and is also called G/478K.V1. It has an estimated 97% increase of transmissibility.POLYMORPHISM Variant Omicron/BA.1 and BA.2 belong to a lineage first isolated in South Africa (November 2021).SIMILARITY Belongs to the betacoronaviruses M protein family. Severe acute respiratory syndrome coronavirus 2 NCBI Taxonomy 2697049 UniProt P0DTC5 1 EQUAL 221 EQUAL Reactome DB_ID: 61459 1 1 EQUAL 556 EQUAL Reactome DB_ID: 9694702 1 N dimer [cytosol] N dimer Reactome DB_ID: 9729340 2 UniProt:P0DTC9 N N N FUNCTION Packages the positive strand viral genome RNA into a helical ribonucleocapsid (RNP) and plays a fundamental role during virion assembly through its interactions with the viral genome and membrane protein M. Plays an important role in enhancing the efficiency of subgenomic viral RNA transcription as well as viral replication (By similarity).FUNCTION May induce inflammasome responses in cultured cells and mice. Acts by interacting with host NLRP3 to facilitate inflammasome assembly, which induces cytokine release that may play a role in COVID lung injury.SUBUNIT Homooligomer. Both monomeric and oligomeric forms interact with RNA. Interacts with protein M. Interacts with protein E. Interacts with NSP3; this interaction serves to tether the genome to the newly translated replicase-transcriptase complex at a very early stage of infection (By similarity). May interact with host NLRP3 (PubMed:34341353).PTM ADP-ribosylated. The ADP-ribosylation is retained in the virion during infection.PTM Phosphorylated on serine and threonine residues.POLYMORPHISM Variant Alpha/B.1.1.7 belongs to a lineage isolated first in United Kingdom (December 2020). It is also called Variant of Concern (VOC) 202012/01, Variant Under Investigation (VUI) 202012/01, 501Y.V1 or 20B/501Y.V1.POLYMORPHISM Variant Omicron/BA.1 and BA.2 belong to a lineage first isolated in South Africa (November 2021).SIMILARITY Belongs to the betacoronavirus nucleocapsid protein family. UniProt P0DTC9 sumoylated lysine (monoSUMO1 [cytosol]) at 61 61 EQUAL sumoylated lysine adenosine diphosphoribosyl (ADP-ribosyl) modified residue at unknown position adenosine diphosphoribosyl (ADP-ribosyl) modified residue O-phospho-L-serine at 188 188 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 206 206 EQUAL O-phospho-L-serine at 176 176 EQUAL O-phospho-L-serine at 180 180 EQUAL O-phospho-L-serine at 184 184 EQUAL O-phospho-L-serine at 194 194 EQUAL O-phospho-L-threonine at 198 198 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-serine at 202 202 EQUAL O-phospho-L-serine at 201 201 EQUAL O-phospho-L-threonine at 205 205 EQUAL O-phospho-L-serine at 23 23 EQUAL O-phospho-L-serine at 79 79 EQUAL O-phospho-L-serine at 183 183 EQUAL omega-N-methyl-L-arginine at 95 95 EQUAL omega-N-methyl-L-arginine omega-N-methyl-L-arginine at 177 177 EQUAL 2 EQUAL 422 EQUAL Reactome Database ID Release 82 9694702 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9694702 Reactome R-COV-9694702 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-COV-9694702.3 Reactome Database ID Release 82 9755778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9755778 Reactome R-HSA-9755778 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9755778.1 AKT phosphorylates targets in the cytosol AKT phosphorylates targets in the cytosol 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). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Edited: Jassal, B, 2011-05-11 2.7.11.1 AKT phosphorylates BAD AKT phosphorylates BAD Activated AKT phosphorylates the BCL-2 family member BAD at serine 99 (corresponds to serine residue S136 of mouse Bad), blocking the BAD-induced cell death (Datta et al. 1997, del Peso et al. 1997, Khor et al. 2004). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 50662 1 UniProt:Q92934 BAD BAD BCL2L8 BAD BBC6 FUNCTION Promotes cell death. Successfully competes for the binding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the level of heterodimerization of these proteins with BAX. Can reverse the death repressor activity of Bcl-X(L), but not that of Bcl-2 (By similarity). Appears to act as a link between growth factor receptor signaling and the apoptotic pathways.SUBUNIT Forms heterodimers with the anti-apoptotic proteins, Bcl-X(L), Bcl-2 and Bcl-W. Also binds protein S100A10 (By similarity). The Ser-75/Ser-99 phosphorylated form binds 14-3-3 proteins (By similarity). Interacts with AKT1 and PIM3. Interacts (via BH3 domain) with NOL3 (via CARD domain); preventing the association of BAD with BCL2 (By similarity). Interacts with HIF3A (via C-terminus domain); the interaction reduces the binding between BAD and BAX (By similarity). Interacts with GIMAP3/IAN4 and GIMAP5/IAN5 (PubMed:16509771).TISSUE SPECIFICITY Expressed in a wide variety of tissues.DOMAIN Intact BH3 motif is required by BIK, BID, BAK, BAD and BAX for their pro-apoptotic activity and for their interaction with anti-apoptotic members of the Bcl-2 family.PTM Phosphorylated on one or more of Ser-75, Ser-99, Ser-118 and Ser-134 in response to survival stimuli, which blocks its pro-apoptotic activity. Phosphorylation on Ser-99 or Ser-75 promotes heterodimerization with 14-3-3 proteins. This interaction then facilitates the phosphorylation at Ser-118, a site within the BH3 motif, leading to the release of Bcl-X(L) and the promotion of cell survival. Ser-99 is the major site of AKT/PKB phosphorylation, Ser-118 the major site of protein kinase A (CAPK) phosphorylation. Phosphorylation at Ser-99 by PKB/AKT1 is almost completely blocked by the apoptotic C-terminus cleavage product of PKN2 generated by caspases-3 activity during apoptosis.PTM Methylation at Arg-94 and Arg-96 by PRMT1 inhibits Akt-mediated phosphorylation at Ser-99.SIMILARITY Belongs to the Bcl-2 family.CAUTION The protein name 'Bcl2 antagonist of cell death' may be misleading. The protein antagonises Bcl2-mediated repression of cell death, hence it promotes apoptosis. UniProt Q92934 1 EQUAL 168 EQUAL Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 198335 1 O-phospho-L-serine at 99 99 EQUAL 1 EQUAL 168 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202074 Reactome Database ID Release 82 198368 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198368 Reactome Database ID Release 82 198347 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198347 Reactome R-HSA-198347 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198347.4 9346240 Pubmed 1997 Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery Datta, S R Dudek, H Tao, X Masters, S Fu, H Gotoh, Y Greenberg, M E Cell 91:231-41 9381178 Pubmed 1997 Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt del Peso, L Gonzalez-Garcia, M Page, Clive P Herrera, R Nunez, G Science 278:687-9 15183529 Pubmed 2004 Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 15183529 Khor, TO Gul, YA Ithnin, H Seow, HF Cancer Lett 210:139-50 GO 0043491 GO biological process 2.7.11.1 AKT phosphorylates GSK3 AKT phosphorylates GSK3 GSK3 (glycogen synthase kinase-3) participates in the Wnt signaling pathway. It is implicated in the hormonal control of several regulatory proteins including glycogen synthase, and the transcription factors MYB and JUN. GSK3 phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. GSK3 is inhibited when phosphorylated by AKT1. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 113592 1 Converted from EntitySet in Reactome Reactome DB_ID: 198358 1 GSK3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GSK3B [cytosol] GSK3A [cytosol] UniProt P49841 UniProt P49840 Converted from EntitySet in Reactome Reactome DB_ID: 198373 1 p-S9/21-GSK3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-S21-GSK3A [cytosol] p-S9-GSK3B [cytosol] Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202074 Reactome Database ID Release 82 198371 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198371 Reactome R-HSA-198371 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198371.3 2.7.11.1 AKT phosphorylates caspase-9 AKT phosphorylates caspase-9 AKT can phosphorylate the apoptotic protease caspase-9, inhibiting it. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 57033 1 UniProt:P55211 CASP9 CASP9 CASP9 MCH6 FUNCTION Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates caspase-3. Promotes DNA damage-induced apoptosis in a ABL1/c-Abl-dependent manner. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP).FUNCTION Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9.ACTIVITY REGULATION Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis.SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 35 kDa (p35) and a 10 kDa (p10) subunit. Caspase-9 and APAF1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome C and ATP. Interacts (inactive form) with EFHD2. Interacts with HAX1. Interacts with BIRC2/c-IAP1, XIAP/BIRC4, BIRC5/survivin, BIRC6/bruce and BIRC7/livin. Interacts with ABL1 (via SH3 domain); the interaction is direct and increases in the response of cells to genotoxic stress and ABL1/c-Abl activation. Interacts with BCL2L10 (PubMed:19255499). Interacts with NleF from pathogenic E.coli.TISSUE SPECIFICITY Ubiquitous, with highest expression in the heart, moderate expression in liver, skeletal muscle, and pancreas. Low levels in all other tissues. Within the heart, specifically expressed in myocytes.DEVELOPMENTAL STAGE Expressed at low levels in fetal heart, at moderate levels in neonate heart, and at high levels in adult heart.PTM Cleavages at Asp-315 by granzyme B and at Asp-330 by caspase-3 generate the two active subunits. Caspase-8 and -10 can also be involved in these processing events.PTM Phosphorylated at Thr-125 by MAPK1/ERK2. Phosphorylation at Thr-125 is sufficient to block caspase-9 processing and subsequent caspase-3 activation. Phosphorylation on Tyr-153 by ABL1/c-Abl; occurs in the response of cells to DNA damage.SIMILARITY Belongs to the peptidase C14A family. UniProt P55211 1 EQUAL 416 EQUAL Reactome DB_ID: 113592 1 Reactome DB_ID: 198636 1 O-phospho-L-serine at 196 196 EQUAL 1 EQUAL 416 EQUAL Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202074 Reactome Database ID Release 82 198621 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198621 Reactome R-HSA-198621 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198621.5 9812896 Pubmed 1998 Regulation of cell death protease caspase-9 by phosphorylation Cardone, MH Roy, N Stennicke, HR Salvesen, Guy S. Franke, TF Stanbridge, E Frisch, S Reed, JC Science 282:1318-21 2.7.11.1 AKT phosphorylates MDM2 AKT phosphorylates MDM2 AKT phosphorylates MDM2 on two serine residues, at positions 166 and 188 (Mayo and Donner 2001, Feng et al. 2004, Milne et al. 2004). AKT-mediated phosphorylation of the E3 ubiquitin-protein ligase MDM2 promotes nuclear localization and interferes with the interaction between MDM2 and p14-ARF, thereby decreasing p53 stability. This leads to a decreased expression of p53 target genes, such as BAX, that promote apoptosis (Zhou et al. 2001, Mayo and Donner 2001). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Reactome DB_ID: 198644 1 UniProt:Q00987 MDM2 MDM2 MDM2 FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also a component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation (PubMed:12821780, PubMed:15053880, PubMed:15195100, PubMed:15632057, PubMed:16337594, PubMed:17290220, PubMed:19098711, PubMed:19219073, PubMed:19837670, PubMed:19965871, PubMed:20173098, PubMed:20385133, PubMed:20858735, PubMed:22128911). Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells (By similarity). Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis (By similarity). Negatively regulates NDUFS1, leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis (PubMed:30879903). Binds NDUFS1 leading to its cytosolic retention rather than mitochondrial localization resulting in decreased supercomplex assembly (interactions between complex I and complex III), decreased complex I activity, ROS production, and apoptosis (PubMed:30879903).SUBUNIT Interacts with p53/TP53, TP73/p73, RBL5 and RP11. Binds specifically to RNA. Can interact with RB1, E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with p53/TP53 and WWOX. Interacts with CDKN2AIP, RFWD3, USP7, PYHIN1, and RBBP6. Interacts with ARRB1 and ARRB2. Interacts with PSMA3. Found in a trimeric complex with MDM2, MDM4 and USP2. Interacts with USP2 (via N-terminus and C-terminus). Interacts with MDM4. Part of a complex with MDM2, DAXX, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7. Interacts directly with DAXX and USP7. Interacts (via C-terminus) with RASSF1 isoform A (via N-terminus); the interaction is independent of TP53. Interacts with APEX1; leading to its ubiquitination and degradation. Interacts with RYBP; this inhibits ubiquitination of TP53. Identified in a complex with RYBP and p53/TP53. Also a component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in regulating p53/TP53 stabilization and activity. Binds directly both p53/TP53 and TRIM28. Component of the TRIM28/KAP1-ERBB4-MDM2 complex involved in connecting growth factor responses with DNA damage. Interacts directly with both TRIM28 and ERBB4 in the complex. Interacts with DYRK2. Interacts with IGF1R. Interacts with TRIM13; the interaction ubiquitinates MDM2 leading to its proteasomal degradation. Interacts with SNAI1; this interaction promotes SNAI1 ubiquitination. Interacts with NOTCH1 (via intracellular domain). Interacts with FHIT. Interacts with RFFL and RNF34; the interaction stabilizes MDM2. Interacts with CDK5RAP3 and CDKN2A/ARF; form a ternary complex involved in regulation of p53/TP53 (PubMed:16173922). Interacts with MTA1. Interacts with AARB2. Interacts with MTBP. Interacts with PML. Interacts with TBRG1. Interacts with the 5S RNP which is composed of the 5S RNA, RPL5 and RPL11; the interaction is direct, occurs in the nucleoplasm and negatively regulates MDM2-mediated TP53 ubiquitination and degradation (PubMed:15195100, PubMed:24120868). Interacts with ADGRB1; the interaction results in inhibition of MDM2-mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4 stability and regulating synaptic plasticity (By similarity). Interacts with RPL23A; this interaction may promote p53/TP53 polyubiquitination (PubMed:26203195). Interacts with NDUFS1 (PubMed:30879903).SUBUNIT (Microbial infection) Interacts with herpes virus 8 protein v-IRF4.SUBUNIT (Microbial infection) Interacts with and ubiquitinates HIV-1 Tat.TISSUE SPECIFICITY Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues.INDUCTION By DNA damage.DOMAIN Region I is sufficient for binding p53 and inhibiting its G1 arrest and apoptosis functions. It also binds p73 and E2F1. Region II contains most of a central acidic region required for interaction with ribosomal protein L5 and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc interacts specifically with RNA whether or not zinc is present and mediates the heterooligomerization with MDM4. It is also essential for its ubiquitin ligase E3 activity toward p53 and itself.PTM Phosphorylation on Ser-166 by SGK1 activates ubiquitination of p53/TP53. Phosphorylated at multiple sites near the RING domain by ATM upon DNA damage; this prevents oligomerization and E3 ligase processivity and impedes constitutive p53/TP53 degradation.PTM Autoubiquitination leads to proteasomal degradation; resulting in p53/TP53 activation it may be regulated by SFN. Also ubiquitinated by TRIM13. Deubiquitinated by USP2 leads to its accumulation and increases deubiquitination and degradation of p53/TP53. Deubiquitinated by USP7 leading to its stabilization.POLYMORPHISM A polymorphism in the MDM2 promoter is associated with susceptibility to accelerated tumor formation in both hereditary and sporadic cancers [MIM:614401]. It also contributes to susceptibility to Li-Fraumeni syndrome, in patients carrying a TP53 germline mutation.DISEASE Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.MISCELLANEOUS MDM2 RING finger mutations that failed to ubiquitinate p53 in vitro did not target p53 for degradation when expressed in cells.SIMILARITY Belongs to the MDM2/MDM4 family.CAUTION Was reported to interact with UBXN6 but the corresponding article has been retracted (PubMed:18768758).CAUTION A report observed N-glycosylation at Asn-349 (PubMed:19139490). However, as the protein is not extracellular, additional evidence is required to confirm this result. UniProt Q00987 1 EQUAL 491 EQUAL Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 198638 1 O-phospho-L-serine at 166 166 EQUAL O-phospho-L-serine at 188 188 EQUAL 1 EQUAL 491 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202074 Reactome Database ID Release 82 198599 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198599 Reactome R-HSA-198599 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198599.5 15169778 Pubmed 2004 Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation Feng, Jianhua Tamaskovic, Rastislav Yang, Zhongzhou Brazil, Derek P Merlo, Adrian Hess, Daniel Hemmings, BA J. Biol. Chem. 279:35510-7 15527798 Pubmed 2004 A novel site of AKT-mediated phosphorylation in the human MDM2 onco-protein Milne, Diane Kampanis, Petros Nicol, Samantha Dias, Sylvia Campbell, David G Fuller-Pace, Frances Meek, David FEBS Lett. 577:270-6 11504915 Pubmed 2001 A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus Mayo, L D Donner, D B Proc. Natl. Acad. Sci. U.S.A. 98:11598-603 11715018 Pubmed 2001 HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation Zhou, BP Liao, Y Xia, W Zou, Y Spohn, B Hung, MC Nat Cell Biol 3:973-82 2.7.11.1 AKT phosphorylates IKKalpha AKT phosphorylates IKKalpha AKT mediates IKKalpha (Inhibitor of nuclear factor kappa B kinase subunit alpha) phosphorylation at threonine 23, which is required for NF-kB activation. NF-kB promoted gene transcription enhances neuronal survival. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 113592 1 Reactome DB_ID: 168104 1 UniProt:O15111 CHUK CHUK TCF16 CHUK IKKA FUNCTION Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11) (PubMed:21765415). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes (PubMed:20501937). In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities (PubMed:17434128). Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP (PubMed:12789342). Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates AMBRA1 following mitophagy induction, promoting AMBRA1 interaction with ATG8 family proteins and its mitophagic activity (PubMed:30217973).ACTIVITY REGULATION Activated when phosphorylated and inactivated when dephosphorylated.SUBUNIT Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits (PubMed:32935379). The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:10195894, PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Directly interacts with TRPC4AP (By similarity). May interact with TRAF2 (PubMed:19150425). Interacts with NALP2 (PubMed:15456791). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity (PubMed:20434986). Interacts with PIAS1; this interaction induces PIAS1 phosphorylation (PubMed:17540171). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with FOXO3 (PubMed:15084260). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14 (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Directly interacts with DDX3X after the physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation (PubMed:30341167).SUBUNIT (Microbial infection) Interacts with InlC of Listeria monocytogenes.TISSUE SPECIFICITY Widely expressed.DOMAIN The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.PTM Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.PTM (Microbial infection) Acetylation of Thr-179 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. UniProt O15111 1 EQUAL 745 EQUAL Reactome DB_ID: 29370 1 Reactome DB_ID: 198615 1 O-phospho-L-threonine at 23 23 EQUAL 1 EQUAL 745 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202074 Reactome Database ID Release 82 198611 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198611 Reactome R-HSA-198611 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198611.4 10485710 Pubmed 1999 NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase Ozes, ON Mayo, LD Gustin, JA Pfeffer, SR Pfeffer, LM Donner, DB Nature 401:82-5 2.7.11.1 AKT phosphorylates p21Cip1 and p27Kip1 AKT phosphorylates p21Cip1 and p27Kip1 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. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Converted from EntitySet in Reactome Reactome DB_ID: 182504 1 CDKN1A,CDKN1B [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CDKN1B [cytosol] CDKN1A [cytosol] UniProt P46527 UniProt P38936 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Converted from EntitySet in Reactome Reactome DB_ID: 198605 1 p-T-CDKN1A/B [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-T157-CDKN1B [cytosol] p-T145-CDKN1A [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202074 Reactome Database ID Release 82 198613 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198613 Reactome R-HSA-198613 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198613.5 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 2.7.11.1 AKT phosphorylates TSC2, inhibiting it AKT phosphorylates TSC2, inhibiting it AKT phosphorylates and inhibits TSC2 (tuberin), a suppressor of the TOR kinase pathway, which senses nutrient levels in the environment. TSC2 forms a protein complex with TSC1 and this complex acts as a GAP (GTPase activating protein) for the RHEB G-protein. RHEB, in turn, activates the TOR kinase. Thus, an active AKT1 activates the TOR kinase, both of which are positive signals for cell growth (an increase in cell mass) and division.<br>The TOR kinase regulates two major processes: translation of selected mRNAs in the cell and autophagy. In the presence of high nutrient levels TOR is active and phosphorylates the 4EBP protein releasing the eukaryotic initiation factor 4E (eIF4E), which is essential for cap-dependent initiation of translation and promoting growth of the cell (PMID: 15314020). TOR also phosphorylates the S6 kinase, which is implicated in ribosome biogenesis as well as in the modification of the S6 ribosomal protein. AKT can also activate mTOR by another mechanism, involving phosphorylation of PRAS40, an inhibitor of mTOR activity. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Inga, Alberto, 2016-02-04 Reviewed: Zaccara, Sara, 2016-02-04 Edited: Orlic-Milacic, Marija, 2014-12-23 Reactome DB_ID: 2980548 1 UniProt:P49815 TSC2 TSC2 TSC4 TSC2 FUNCTION In complex with TSC1, this tumor suppressor inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400). Acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 (PubMed:15340059). May also play a role in microtubule-mediated protein transport (By similarity). Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 (By similarity).SUBUNIT Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex thereby stabilizing TSC2 (PubMed:29127155). Interacts with TSC1 and HERC1; the interaction with TSC1 stabilizes TSC2 and prevents the interaction with HERC1 (PubMed:9580671, PubMed:10585443, PubMed:15963462, PubMed:16464865). May also interact with the adapter molecule RABEP1 (PubMed:9045618). The final complex may contain TSC2 and RABEP1 linked to RAB5 (PubMed:9045618). Interacts with HSPA1 and HSPA8 (PubMed:15963462). Interacts with DAPK1 (PubMed:18974095). Interacts with FBXW5 (PubMed:18381890). Interacts with NAA10 (via C-terminal domain) (PubMed:20145209). Interacts with RRAGA (polyubiquitinated) (PubMed:25936802). Interacts with WDR45B (PubMed:28561066). Interacts with RPAP3 and URI1 (PubMed:28561026). Interacts with YWHAG (PubMed:33473107).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL38; this interaction inhibits cellular stress response mediated by mTORC1.TISSUE SPECIFICITY Liver, brain, heart, lymphocytes, fibroblasts, biliary epithelium, pancreas, skeletal muscle, kidney, lung and placenta.PTM Phosphorylation at Ser-1387, Ser-1418 or Ser-1420 does not affect interaction with TSC1. Phosphorylation at Ser-939 and Thr-1462 by PKB/AKT1 is induced by growth factor stimulation. Phosphorylation by AMPK activates it and leads to negative regulation of the mTORC1 complex. Phosphorylated at Ser-1798 by RPS6KA1; phosphorylation inhibits TSC2 ability to suppress mTORC1 signaling. Phosphorylated by DAPK1.PTM Ubiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase complex, leading to its subsequent degradation. Ubiquitinated by MYCBP2 independently of its phosphorylation status leading to subsequent degradation; association with TSC1 protects from ubiquitination. UniProt P49815 1 EQUAL 1807 EQUAL Reactome DB_ID: 113592 2 Reactome DB_ID: 199484 1 O-phospho-L-serine at 939 939 EQUAL O-phospho-L-threonine at 1462 1462 EQUAL 1 EQUAL 1807 EQUAL Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202074 Reactome Database ID Release 82 198609 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198609 Reactome R-HSA-198609 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198609.5 12150915 Pubmed 2002 Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway Manning, BD Tee, AR Logsdon, MN Blenis, J Cantley, Lewis C Mol Cell 10:151-62 12172553 Pubmed 2002 TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling Inoki, K Li, Yun Zhu, T Wu, J Guan, KL Nat Cell Biol 4:648-57 2.7.11.1 AKT phosphorylates AKT1S1 (PRAS40) AKT phosphorylates AKT1S1 (PRAS40) PRAS40 (proline-rich Akt/PKB substrate 40 kDa) is a substrate of AKT, the phosphorylation of which leads to the binding of this protein to 14-3-3. PRAS40 binds to mTOR complexes, mediating AKT signals to mTOR. Interaction of PRAS40 with the mTOR kinase domain is induced under conditions that inhibit mTOR signalling, such as growth factor deprivation. Binding of PRAS40 inhibits mTOR. PRAS40 phosphorylation by AKT and association with the cytosolic anchor protein 14-3-3, lead to mTOR stimulation (Vander Haar E, et al, 2007). Although it was originally identified in the context of insulin signalling, it was later shown that PRAS40 may also play a role in nerve growth factor-mediated neuroprotection (Saito A, et al, 2004). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 200155 1 UniProt:Q96B36 AKT1S1 AKT1S1 PRAS40 AKT1S1 FUNCTION Subunit of mTORC1, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, AKT1S1 negatively regulates mTOR activity in a manner that is dependent on its phosphorylation state and binding to 14-3-3 proteins. Inhibits RHEB-GTP-dependent mTORC1 activation. Substrate for AKT1 phosphorylation, but can also be activated by AKT1-independent mechanisms. May also play a role in nerve growth factor-mediated neuroprotection.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin. Interacts directly with RPTOR. The phosphorylated form interacts with 14-3-3 proteins.TISSUE SPECIFICITY Widely expressed with highest levels of expression in liver and heart. Expressed at higher levels in cancer cell lines (e.g. A-549 and HeLa) than in normal cell lines (e.g. HEK293).PTM Phosphorylated by AKT1 (PubMed:12524439). Phosphorylation at Thr-246 by DYRK3 relieves inhibitory function on mTORC1 (PubMed:23415227). UniProt Q96B36 1 EQUAL 256 EQUAL Reactome DB_ID: 113592 2 Reactome DB_ID: 200163 1 O-phospho-L-serine at 183 183 EQUAL O-phospho-L-threonine at 246 246 EQUAL 1 EQUAL 256 EQUAL Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202074 Reactome Database ID Release 82 200143 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200143 Reactome R-HSA-200143 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200143.4 12524439 Pubmed 2003 Identification of a proline-rich Akt substrate as a 14-3-3 binding partner Kovacina, KS Park, GY Bae, SS Guzzetta, AW Schaefer, E Birnbaum, MJ Roth, RA J Biol Chem 278:10189-94 17277771 Pubmed 2007 Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40 Vander Haar, E Lee, SI Bandhakavi, S Griffin, TJ Kim, DH Nat Cell Biol 9:316-23 14973226 Pubmed 2004 Neuroprotective role of a proline-rich Akt substrate in apoptotic neuronal cell death after stroke: relationships with nerve growth factor Saito, A Narasimhan, P Hayashi, T Okuno, S Ferrand-Drake, M Chan, PH J Neurosci 24:1584-93 2.7.11.1 AKT phosphorylates MKRN1 AKT phosphorylates MKRN1 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). Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Salmena, Leonardo, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-11-16 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 976042 1 UniProt:Q9UHC7 MKRN1 MKRN1 MKRN1 RNF61 FUNCTION E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. These substrates include FILIP1, p53/TP53, CDKN1A and TERT. Keeps cells alive by suppressing p53/TP53 under normal conditions, but stimulates apoptosis by repressing CDKN1A under stress conditions. Acts as a negative regulator of telomerase. Has negative and positive effects on RNA polymerase II-dependent transcription.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with p53/TP53 and CDKN1A. Interacts with TERT, modulating telomere length homeostasis.TISSUE SPECIFICITY Ubiquitous.INDUCTION Frequently induced in esophageal squamous cell carcinoma (SCC) tissues.PTM Auto-ubiquitinated; which leads to proteasomal degradation. UniProt Q9UHC7 1 EQUAL 482 EQUAL Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 8948758 1 O-phospho-L-serine at 109 109 EQUAL 1 EQUAL 482 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202074 Reactome Database ID Release 82 8948757 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948757 Reactome R-HSA-8948757 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948757.2 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 Reactome Database ID Release 82 198323 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198323 Reactome R-HSA-198323 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198323.4 AKT translocates to the nucleus AKT translocates to the nucleus AKT, phosphorylated at threonine (AKT1 308; AKT2 309; AKT3 305) and serine (AKT1 473; AKT2 474; AKT3 472) translocates to the nucleus, reaching a maximum after 15 min and returning to a basal level after 45 min of NGF stimulation. Control of the amount of nuclear AKT is achieved through the action of the phosphatase PP2A (Borgatti et al. 2003). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Converted from EntitySet in Reactome Reactome DB_ID: 202074 1 Converted from EntitySet in Reactome Reactome DB_ID: 202072 1 nucleoplasm GO 0005654 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 p-T308,S473-AKT1 [nucleoplasm] Reactome Database ID Release 82 198298 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198298 Reactome R-HSA-198298 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198298.4 12767043 Pubmed 2003 Threonine 308 phosphorylated form of Akt translocates to the nucleus of PC12 cells under nerve growth factor stimulation and associates with the nuclear matrix protein nucleolin Borgatti, P Martelli, AM Tabellini, G Bellacosa, A Capitani, S Neri, LM J Cell Physiol 196:79-88 AKT phosphorylates targets in the nucleus AKT phosphorylates targets in the nucleus After translocation into the nucleus, AKT can phosphorylate a number of targets there such as CREB, forkhead transcription factors, SRK and NUR77. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 2.7.11.1 AKT phosphorylates CREB1 AKT phosphorylates CREB1 AKT phosphorylates CREB (cAMP response element-binding protein) at serine 133 and activates gene expression via a CREB-dependent mechanism, thus promoting cell survival. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 29358 1 Reactome DB_ID: 52777 1 UniProt:P16220 CREB1 CREB1 CREB1 FUNCTION Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-119 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.SUBUNIT Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. When phosphorylated on Ser-119, binds CREBBP (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity (By similarity). Interacts (phosphorylated form) with TOX3. Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119 (PubMed:15964553). Forms a complex with KMT2A and CREBBP (PubMed:23651431, PubMed:14506290, PubMed:14536081, PubMed:15454081, PubMed:15733869, PubMed:15964553, PubMed:16325578, PubMed:16908542, PubMed:20573984, PubMed:21172805) (By similarity). Interacts with TOX4; CREB1 is required for full induction of TOX4-dependent activity and the interaction is increased by cAMP and inhibited by insulin (By similarity).SUBUNIT (Microbial infection) Interacts with hepatitis B virus/HBV protein X.SUBUNIT (Microbial infection) Interacts with HTLV-1 protein Tax.PTM Stimulated by phosphorylation. Phosphorylation of both Ser-119 and Ser-128 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylation of Ser-119 allows CREBBP binding. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion (By similarity). CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity (By similarity). Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-119. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of Ser-128 blocks CREB-mediated transcription even when Ser-119 is phosphorylated. Phosphorylated by CaMK1 (By similarity). Phosphorylation of Ser-257 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. Phosphorylated by TSSK4 on Ser-119 (PubMed:15964553).PTM Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization.DISEASE A CREB1 mutation has been found in a patient with multiple congenital anomalies consisting of agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia.SIMILARITY Belongs to the bZIP family. UniProt P16220 1 EQUAL 341 EQUAL Reactome DB_ID: 113582 1 Reactome DB_ID: 111910 1 O-phospho-L-serine at 133 133 EQUAL 1 EQUAL 341 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202072 Reactome Database ID Release 82 199274 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199274 Reactome Database ID Release 82 199298 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199298 Reactome R-HSA-199298 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199298.2 9829964 Pubmed 1998 CREB is a regulatory target for the protein kinase Akt/PKB Du, K Montminy, M J Biol Chem 273:32377-9 2.7.11.1 AKT phosphorylates FOXO transcription factors AKT phosphorylates FOXO transcription factors 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). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Donlon, Timothy, 2018-10-17 Reviewed: Bertaggia, Enrico, 2018-10-26 Edited: Orlic-Milacic, Marija, 2018-10-31 Reactome DB_ID: 29358 3 Converted from EntitySet in Reactome Reactome DB_ID: 199272 1 FOXO1,FOXO3,FOXO4,(FOXO6) [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity FOXO4 [nucleoplasm] FOXO3 [nucleoplasm] FOXO1 [nucleoplasm] UniProt P98177 UniProt O43524 UniProt Q12778 Reactome DB_ID: 113582 3 Converted from EntitySet in Reactome Reactome DB_ID: 9614997 1 p-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4,(p-T26,S184-FOXO6) [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-T32,S253,S315-FOXO3 [nucleoplasm] p-T32,S197,S262-FOXO4 [nucleoplasm] p-T24,S256,S319-FOXO1 [nucleoplasm] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202072 Reactome Database ID Release 82 199299 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199299 Reactome R-HSA-199299 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199299.4 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 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 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 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 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 2.7.11.1 AKT can phosphorylate RSK AKT can phosphorylate RSK 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. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 29358 2 Reactome DB_ID: 199877 1 UniProt:Q9UBS0 RPS6KB2 RPS6KB2 STK14B RPS6KB2 FUNCTION Phosphorylates specifically ribosomal protein S6 (PubMed:29750193). Seems to act downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression in an alternative pathway regulated by MEAK7 (PubMed:29750193).PTM Phosphorylated and activated by MTOR. Phosphorylation by PKC within the NLS in response to mitogenic stimuli causes cytoplasmic retention.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily. UniProt Q9UBS0 1 EQUAL 482 EQUAL Reactome DB_ID: 113582 2 Reactome DB_ID: 199844 1 O-phospho-L-serine at 15 15 EQUAL O-phospho-L-serine at 356 356 EQUAL 1 EQUAL 482 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202072 Reactome Database ID Release 82 199839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199839 Reactome R-HSA-199839 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199839.2 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 2.7.11.1 AKT can phosphorylate NR4A1 (NUR77) AKT can phosphorylate NR4A1 (NUR77) 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). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 29358 1 Reactome DB_ID: 199831 1 UniProt:P22736 NR4A1 NR4A1 NR4A1 HMR GFRP1 NAK1 FUNCTION Orphan nuclear receptor. May act concomitantly with NURR1 in regulating the expression of delayed-early genes during liver regeneration. Binds the NGFI-B response element (NBRE) 5'-AAAAGGTCA-3' (By similarity). May inhibit NF-kappa-B transactivation of IL2. Participates in energy homeostasis by sequestrating the kinase STK11 in the nucleus, thereby attenuating cytoplasmic AMPK activation. Plays a role in the vascular response to injury (By similarity).SUBUNIT Binds DNA as a monomer (By similarity). Interacts with GADD45GIP1 (PubMed:15459248). Interacts with STK11 (PubMed:22983157). Interacts with IFI27 (PubMed:22427340). Heterodimer (via DNA-binding domain) with RXRA (via C-terminus); DNA-binding of the heterodimer is enhanced by 9-cis retinoic acid (PubMed:17761950, PubMed:15509776). Competes for the RXRA interaction with EP300 and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950).TISSUE SPECIFICITY Fetal muscle and adult liver, brain and thyroid.INDUCTION By growth-stimulating agents.PTM Phosphorylated at Ser-351 by RPS6KA1 and RPS6KA3 in response to mitogenic or stress stimuli.PTM Acetylated by p300/CBP, acetylation increases stability. Deacetylated by HDAC1.SIMILARITY Belongs to the nuclear hormone receptor family. NR4 subfamily. UniProt P22736 1 EQUAL 598 EQUAL Reactome DB_ID: 199846 1 O-phospho-L-serine at 351 351 EQUAL 1 EQUAL 598 EQUAL Reactome DB_ID: 113582 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202072 Reactome Database ID Release 82 199863 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199863 Reactome R-HSA-199863 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199863.2 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 Reactome Database ID Release 82 198693 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198693 Reactome R-HSA-198693 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198693.2 Negative regulation of the PI3K/AKT network Negative regulation of the PI3K/AKT network The PI3K/AKT network is negatively regulated by phosphatases that dephosphorylate PIP3, thus hampering AKT activation. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 3.1.3.67 PTEN dephosphorylates PIP3 PTEN dephosphorylates PIP3 PI(3,4,5)P3 is dephosphorylated to PI (4,5)P2 by PTEN at the plasma membrane At the plasma membrane, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase aka phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) (Maehama & Dixon 1998, Myers et al. 1998, Das et al. 2003). The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Myers et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase.<br>Early studies indicated that magnesium ion, Mg2+, was needed for the catalytic activity of PTEN isolated from bovine thymus (Kabuyama et al. 1996). Subsequent studies have shown that PTEN was catalytically active in buffers free of magnesium and magnesium was not detected as part of the PTEN crystal (Lee et al. 1999). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Wakelam, Michael, 2012-05-14 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Reviewed: Leslie, Nicholas, 2016-09-30 Reviewed: Kriplani, Nisha, 2016-09-30 Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 179838 1 Reactome DB_ID: 29372 1 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 Reactome DB_ID: 179856 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 199420 UniProt:P60484 PTEN PTEN TEP1 PTEN MMAC1 FUNCTION Tumor suppressor. Acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins. Also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate with order of substrate preference in vitro PtdIns(3,4,5)P3 &gt; PtdIns(3,4)P2 &gt; PtdIns3P &gt; Ins(1,3,4,5)P4 (PubMed:26504226, PubMed:16824732). The lipid phosphatase activity is critical for its tumor suppressor function. Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival. The unphosphorylated form cooperates with MAGI2 to suppress AKT1 activation. Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation. Plays a role as a key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. May be a negative regulator of insulin signaling and glucose metabolism in adipose tissue. The nuclear monoubiquitinated form possesses greater apoptotic potential, whereas the cytoplasmic nonubiquitinated form induces less tumor suppressive ability. In motile cells, suppresses the formation of lateral pseudopods and thereby promotes cell polarization and directed movement.ACTIVITY REGULATION Enzymatic activity is enhanced in the presence of phosphatidylserine.SUBUNIT Monomer. The unphosphorylated form interacts with the second PDZ domain of MAGI2 and with DLG1 and MAST2 in vitro (PubMed:10646847, PubMed:10760291, PubMed:11707428). Interacts with MAGI2, MAGI3, MAST1 and MAST3, but neither with MAST4 nor with DLG5; interaction with MAGI2 increases protein stability (PubMed:10748157, PubMed:15951562). Interacts with NEDD4 (PubMed:17218260). Interacts with NDFIP1 and NDFIP2; in the presence of NEDD4 or ITCH, this interaction promotes PTEN ubiquitination (PubMed:25801959, PubMed:20534535). Interacts (via C2 domain) with FRK (PubMed:19345329). Interacts with USP7; the interaction is direct (PubMed:18716620). Interacts with ROCK1 (By similarity). Interacts with XIAP/BIRC4 (PubMed:19473982). Interacts with STK11; the interaction phosphorylates PTEN (PubMed:15987703). Interacts with PPP1R16B (PubMed:25007873). Interacts with NOP53; regulates PTEN phosphorylation and increases its stability (PubMed:15355975).TISSUE SPECIFICITY Expressed at a relatively high level in all adult tissues, including heart, brain, placenta, lung, liver, muscle, kidney and pancreas.INDUCTION Down-regulated by TGFB1.DOMAIN The C2 domain binds phospholipid membranes in vitro in a Ca(2+)-independent manner; this binding is important for its tumor suppressor function.PTM Constitutively phosphorylated by CK2 under normal conditions. Phosphorylated in vitro by MAST1, MAST2, MAST3 and STK11. Phosphorylation results in an inhibited activity towards PIP3. Phosphorylation can both inhibit or promote PDZ-binding. Phosphorylation at Tyr-336 by FRK/PTK5 protects this protein from ubiquitin-mediated degradation probably by inhibiting its binding to NEDD4. Phosphorylation by ROCK1 is essential for its stability and activity. Phosphorylation by PLK3 promotes its stability and prevents its degradation by the proteasome.PTM Monoubiquitinated; monoubiquitination is increased in presence of retinoic acid. Deubiquitinated by USP7; leading to its nuclear exclusion. Monoubiquitination of one of either Lys-13 and Lys-289 amino acid is sufficient to modulate PTEN compartmentalization. Ubiquitinated by XIAP/BIRC4.DISEASE PTEN mutations are found in a subset of patients with Proteus syndrome, a genetically heterogeneous condition. The molecular diagnosis of PTEN mutation positive cases classifies Proteus syndrome patients as part of the PTEN hamartoma syndrome spectrum. As such, patients surviving the early years of Proteus syndrome are likely at a greater risk of developing malignancies.DISEASE A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome, which shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome.SIMILARITY Belongs to the PTEN phosphatase protein family. UniProt P60484 2 EQUAL 403 EQUAL GO 0016314 GO molecular function Reactome Database ID Release 82 199445 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199445 Reactome Database ID Release 82 199456 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199456 Reactome R-HSA-199456 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199456.4 9593664 Pubmed 1998 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate Maehama, T Dixon, JE J Biol Chem 273:13375-8 8681945 Pubmed 1996 Purification and characterization of the phosphatidylinositol-3,4,5-trisphosphate phosphatase in bovine thymus Kabuyama, Y Nakatsu, N Homma, Y Fukui, Y Eur. J. Biochem. 238:350-6 9811831 Pubmed 1998 The lipid phosphatase activity of PTEN is critical for its tumor supressor function Myers, MP Pass, I Batty, IH van der Kaay, J Stolarov, JP Hemmings, BA Downes, CP Tonks, NK Wigler, Michael H Proc Natl Acad Sci U S A 95:13513-8 10555148 Pubmed 1999 Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association Lee, Jie-Oh Yang, Haijuan Georgescu, Maria-Magdalena Di Cristofano, Antonio Maehama, Tomohiko Shi, Y Dixon, Jack Pandolfi, Pier Pavletich, Nikola Cell 99:323-34 12808147 Pubmed 2003 Membrane-binding and activation mechanism of PTEN Das, S Dixon, JE Cho, W Proc Natl Acad Sci U S A 100:7491-6 GO 0051898 GO biological process THEM4 (CTMP) and/or TRIB3 inhibit AKT phosphorylation THEM4 (CTMP) and/or TRIB3 inhibit AKT phosphorylation 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). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 2317329 1 Converted from EntitySet in Reactome Reactome DB_ID: 2400007 1 Reactome DB_ID: 199453 1 Reactome Database ID Release 82 199443 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199443 Reactome R-HSA-199443 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199443.2 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 3.1.3.16 PHLPP dephosphorylates S473 in AKT PHLPP dephosphorylates S473 in AKT 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. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 29356 1 Converted from EntitySet in Reactome Reactome DB_ID: 202074 1 Reactome DB_ID: 29372 1 Converted from EntitySet in Reactome Reactome DB_ID: 202084 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 p-T308-AKT1 [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 199450 PHLPP (Mn2+ cofactor) [cytosol] PHLPP (Mn2+ cofactor) Converted from EntitySet in Reactome Reactome DB_ID: 2327836 1 PHLPP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHLPP1 [cytosol] PHLPP2 [cytosol] UniProt O60346 UniProt Q6ZVD8 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 199450 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199450 Reactome R-HSA-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-HSA-199450.1 GO 0004722 GO molecular function Reactome Database ID Release 82 199438 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199438 Reactome Database ID Release 82 199425 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199425 Reactome R-HSA-199425 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199425.2 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 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 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling 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. Authored: Orlic-Milacic, Marija, 2015-12-21 Reviewed: Porteu, Françoise, 2016-02-08 Edited: Orlic-Milacic, Marija, 2015-12-21 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 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). Authored: Williams, MG, 2011-10-18 Reviewed: Wakelam, Michael, 2012-05-14 Reviewed: Porteu, Françoise, 2016-02-08 Edited: Williams, MG, 2011-08-12 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: 113592 1 Reactome DB_ID: 179856 1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 1806157 PIP5K1A-C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PIP5K1A [cytosol] PIP5K1B [cytosol] PIP5K1C [cytosol] UniProt Q99755 UniProt O14986 UniProt O60331 GO 0016308 GO molecular function Reactome Database ID Release 82 1806262 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1806262 Reactome Database ID Release 82 1676082 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1676082 Reactome R-HSA-1676082 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1676082.2 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 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 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 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 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 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). Authored: Williams, MG, 2011-10-18 Reviewed: Wakelam, Michael, 2012-05-14 Reviewed: Porteu, Françoise, 2016-02-08 Edited: Williams, MG, 2011-08-12 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: 113592 1 Reactome DB_ID: 179856 1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 1806229 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 1806209 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1806209 Reactome Database ID Release 82 1675776 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1675776 Reactome R-HSA-1675776 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1675776.4 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 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 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 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 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 3.1.3.16 AKT1 dephosphorylation by PP2A-B56-beta,gamma AKT1 dephosphorylation by PP2A-B56-beta,gamma 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). Authored: Orlic-Milacic, Marija, 2015-12-21 Reviewed: Porteu, Françoise, 2016-02-08 Edited: Orlic-Milacic, Marija, 2015-12-21 Reactome DB_ID: 198356 1 UniProt:P31749 AKT1 AKT1 RAC PKB AKT1 FUNCTION AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (By similarity). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (By similarity). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (PubMed:11994271). AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity (By similarity). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (By similarity). AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase) (PubMed:11154276). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis (PubMed:11154276). AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating the TORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1 (PubMed:12150915). Also regulates the TORC1 signaling pathway by catalyzing phosphorylation of CASTOR1 (PubMed:33594058). AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization (PubMed:10358075). In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319' (PubMed:10358075). FOXO3 and FOXO4 are phosphorylated on equivalent sites (PubMed:10358075). AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein) (PubMed:9829964). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1 (PubMed:9829964). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (By similarity). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) (PubMed:12176338, PubMed:12964941). AKT mediates the antiapoptotic effects of IGF-I (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). May be involved in the regulation of the placental development (By similarity). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3 (PubMed:17726016). Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation (PubMed:20086174, PubMed:20231902). Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (PubMed:19592491). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity (PubMed:10576742). Phosphorylation of BAD stimulates its pro-apoptotic activity (PubMed:10926925). Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 (PubMed:23431171). Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility (PubMed:20471940). Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation (PubMed:18507042). Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization (PubMed:16982699). These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation (PubMed:16139227). Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (PubMed:20682768). Phosphorylates PCK1 at 'Ser-90', reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor (PubMed:32322062). Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity (PubMed:32228865).ACTIVITY REGULATION Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation (PubMed:20481595, PubMed:21392984, PubMed:9512493, PubMed:9736715). Inhibited by pyrrolopyrimidine inhibitors like aniline triazole and spiroindoline (PubMed:18456494, PubMed:20810279).SUBUNIT Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts (via the C-terminus) with CCDC88A (via its C-terminus). Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE-binding (By similarity). Interacts with AGAP2 (isoform 2/PIKE-A); the interaction occurs in the presence of guanine nucleotides. Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with CDKN1B; the interaction phosphorylates CDKN1B promoting 14-3-3 binding and cell-cycle progression. Interacts with MAP3K5 and TRAF6. Interacts with BAD, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with RAF1. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with TNK2 and CLK2. Interacts (via the C-terminus) with THEM4 (via its C-terminus). Interacts with and phosphorylated by PDPK1. Interacts with PA2G4 (By similarity). Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation (PubMed:24784001). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529). Forms a complex with WDFY2 and FOXO1 (By similarity). Interacts with FAM168A (PubMed:23251525). Interacts with SYAP1 (via phosphorylated form and BSD domain); this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1 (PubMed:23300339). Interacts with PKHM3 (By similarity). Interacts with FKBP5/FKBP51; promoting interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1 (PubMed:28147277). Interacts with TMEM175; leading to formation of the lysoK(GF) complex (PubMed:32228865). Acts as a negative regulator of the cGAS-STING pathway by mediating phosphorylation of CGAS during mitosis, leading to its inhibition (PubMed:26440888).TISSUE SPECIFICITY Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages.DOMAIN Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction.DOMAIN The AGC-kinase C-terminal mediates interaction with THEM4.PTM O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1. O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site.PTM Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity (PubMed:12149249, PubMed:14761976, PubMed:15047712, PubMed:16266983, PubMed:17013611, PubMed:20978158, PubMed:9736715, PubMed:23799035, PubMed:8978681, PubMed:28147277). Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA (PubMed:20333297). This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation (PubMed:9512493). Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1 (PubMed:21464307, PubMed:8978681). Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1 (PubMed:15718470, PubMed:18456494, PubMed:20481595, PubMed:8978681). Ser-473 phosphorylation is enhanced by interaction with AGAP2 isoform 2 (PIKE-A) (PubMed:14761976). Ser-473 phosphorylation is enhanced in focal cortical dysplasias with Taylor-type balloon cells (PubMed:17013611). Ser-473 phosphorylation is enhanced by signaling through activated FLT3 (By similarity). Ser-473 is dephosphorylated by PHLPP (PubMed:28147277). Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase (PubMed:21329884). The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase (PubMed:21329884). Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (PubMed:9512493).PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation (PubMed:19713527). When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated (PubMed:20059950). When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome (PubMed:20059950). Also ubiquitinated by TRIM13 leading to its proteasomal degradation (PubMed:21333377). Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation (PubMed:22410793). Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome (By similarity).PTM Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition.PTM Cleavage by caspase-3/CASP3 (By similarity). Cleaved at the caspase-3 consensus site Asp-462 during apoptosis, resulting in down-regulation of the AKT signaling pathway and decreased cell survival (PubMed:23152800).DISEASE Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION PUBMED:19940129 has been retracted because the same data were used to represent different experimental conditions.CAUTION In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain. O-phospho-L-threonine at 308 308 EQUAL O-phospho-L-serine at 473 473 EQUAL 1 EQUAL 480 EQUAL Reactome DB_ID: 29356 2 Reactome DB_ID: 29372 2 Reactome DB_ID: 58252 1 1 EQUAL 480 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 6811526 PP2A-B56-beta,gamma [cytosol] PP2A-B56-beta,gamma Converted from EntitySet in Reactome Reactome DB_ID: 165977 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: 6811516 1 PPP2R5B,PPP2R5C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PPP2R5B [cytosol] PPP2R5C [cytosol] UniProt Q15173 UniProt Q13362 Converted from EntitySet in Reactome Reactome DB_ID: 165990 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 6811526 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6811526 Reactome R-HSA-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-HSA-6811526.1 Reactome Database ID Release 82 6811478 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6811478 Reactome Database ID Release 82 6811504 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6811504 Reactome R-HSA-6811504 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6811504.5 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 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 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 INHIBITION Reactome Database ID Release 82 6811496 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6811496 Reactome R-HSA-6811496 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6811496.2 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 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. Authored: Orlic-Milacic, Marija, 2016-02-16 Reviewed: Porteu, Françoise, 2016-02-08 Edited: Orlic-Milacic, Marija, 2016-02-16 Reactome DB_ID: 196206 1 PP2A [cytosol] PP2A Converted from EntitySet in Reactome Reactome DB_ID: 165977 1 Converted from EntitySet in Reactome Reactome DB_ID: 196216 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: 165990 1 Reactome Database ID Release 82 196206 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=196206 Reactome R-HSA-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-HSA-196206.1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 8857938 1 p-Y307-PP2A [cytosol] p-Y307-PP2A Converted from EntitySet in Reactome Reactome DB_ID: 196216 1 Converted from EntitySet in Reactome Reactome DB_ID: 165990 1 Converted from EntitySet in Reactome Reactome DB_ID: 8857933 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 8857938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8857938 Reactome R-HSA-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-HSA-8857938.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 8857936 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 8857931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8857931 Reactome Database ID Release 82 8857925 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8857925 Reactome R-HSA-8857925 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8857925.3 ACTIVATION Reactome Database ID Release 82 8858024 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8858024 Reactome R-HSA-8858024 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8858024.2 Reactome DB_ID: 1806240 IER3 recruits MAPKs to PP2A-B56-beta,gamma IER3 recruits MAPKs to PP2A-B56-beta,gamma IEX1 recruits ERKs to PP2A IER3 (IEX-1) recruits both an activated MAPK (MAPK1 (ERK2) or MAPK3 (ERK1)) and the protein phosphatase 2A (PP2A) complex containing regulatory subunits B56-beta (PPP2R5B) or B56-gamma (PPP2R5C), through an interaction with the B56 subunit, forming a tripartite complex (Letourneux et al. 2006, Rocher et al. 2007). Authored: Orlic-Milacic, Marija, 2015-12-21 Reviewed: Porteu, Françoise, 2016-02-08 Edited: Orlic-Milacic, Marija, 2015-12-21 Converted from EntitySet in Reactome Reactome DB_ID: 1268261 1 p-T,Y MAPK dimers [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 6811526 1 Reactome DB_ID: 6811515 1 UniProt:P46695 IER3 IER3 DIF2 IEX1 PRG1 IER3 FUNCTION May play a role in the ERK signaling pathway by inhibiting the dephosphorylation of ERK by phosphatase PP2A-PPP2R5C holoenzyme. Acts also as an ERK downstream effector mediating survival. As a member of the NUPR1/RELB/IER3 survival pathway, may provide pancreatic ductal adenocarcinoma with remarkable resistance to cell stress, such as starvation or gemcitabine treatment.SUBUNIT Interacts with the PPP2R5C-PP2A holoenzyme and ERK kinases; regulates ERK dephosphorylation.INDUCTION By radiation, 12-O-tetradecanoyl phorbol-13 acetate (TPA), okadaic acid, TNF and NUPR1.PTM Phosphorylated at Thr-18, Thr-123 and Ser-126 by MAPK1/ERK2 and probably MAPK3/ERK1. Upon phosphorylation by MAPK1/ERK2 and MAPK3/ERK1, acquires the ability to inhibit cell death induced by various stimuli.PTM Glycosylated.SIMILARITY Belongs to the IER3 family. UniProt P46695 1 EQUAL 156 EQUAL Reactome DB_ID: 6811477 1 PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimers [cytosol] PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimers PP2A:IEX1:p-T,Y-ERKs Converted from EntitySet in Reactome Reactome DB_ID: 1268261 1 Reactome DB_ID: 6811526 1 Reactome DB_ID: 6811515 1 1 EQUAL 156 EQUAL Reactome Database ID Release 82 6811477 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6811477 Reactome R-HSA-6811477 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6811477.1 Reactome Database ID Release 82 6811472 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6811472 Reactome R-HSA-6811472 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6811472.1 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 2.7.11.1 MAPKs phosphorylate PP2A MAPKs phosphorylate PP2A Activated MAPK1 (ERK2) or MAPK3 (ERK1), recruited to the PP2A complex through IER3 (IEX-1), phosphorylate the regulatory subunit PPP2R5B (B56-beta) or PPP2R5C (B56-gamma) of the PP2A complex on serine residue S368 or S337, respectively. ERK-mediated phosphorylation of the PP2A regulatory subunits causes dissociation of the PP2A complex and prevents PP2A-mediated dephosphorylation of AKT1 (Letourneux et al. 2006, Rocher et al. 2007). Authored: Orlic-Milacic, Marija, 2015-12-21 Reviewed: Porteu, Françoise, 2016-02-08 Edited: Orlic-Milacic, Marija, 2015-12-21 Reactome DB_ID: 6811477 1 Reactome DB_ID: 113592 1 Converted from EntitySet in Reactome Reactome DB_ID: 1268261 1 Converted from EntitySet in Reactome Reactome DB_ID: 6811475 1 p-S368-PPP2R5B,p-S337-PPP2R5C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-S368-PPP2R5B [cytosol] p-S337-PPP2R5C [cytosol] Reactome DB_ID: 6811485 1 PP2A-A:PP2A-C [cytosol] PP2A-A:PP2A-C Converted from EntitySet in Reactome Reactome DB_ID: 165977 1 Converted from EntitySet in Reactome Reactome DB_ID: 165990 1 Reactome Database ID Release 82 6811485 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6811485 Reactome R-HSA-6811485 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6811485.1 Reactome DB_ID: 29370 1 Reactome DB_ID: 6811515 1 1 EQUAL 156 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 6811477 Reactome Database ID Release 82 6811498 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6811498 Reactome Database ID Release 82 6811454 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6811454 Reactome R-HSA-6811454 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6811454.1 Reactome Database ID Release 82 6811558 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6811558 Reactome R-HSA-6811558 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6811558.2 GO 0014066 GO biological process Reactome Database ID Release 82 199418 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199418 Reactome R-HSA-199418 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199418.3 PDPK1 binds PIP2 PDPK1 binds PIP2 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). Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 179856 1 Reactome DB_ID: 202210 1 1 EQUAL 556 EQUAL Reactome DB_ID: 2219520 1 PDPK1:PIP2 [plasma membrane] PDPK1:PIP2 Reactome DB_ID: 179856 1 Reactome DB_ID: 61459 1 1 EQUAL 556 EQUAL Reactome Database ID Release 82 2219520 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2219520 Reactome R-HSA-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-HSA-2219520.1 Reactome Database ID Release 82 2219524 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2219524 Reactome R-HSA-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-HSA-2219524.1 PTEN Regulation PTEN Regulation 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). Authored: Orlic-Milacic, Marija, 2015-10-29 Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Reviewed: Leslie, Nicholas, 2016-09-30 Reviewed: Kriplani, Nisha, 2016-09-30 Edited: Orlic-Milacic, Marija, 2017-05-09 Regulation of PTEN gene transcription Regulation of PTEN gene transcription 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). Authored: Orlic-Milacic, Marija, 2015-10-29 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Salmena, Leonardo, 2016-08-11 Edited: Orlic-Milacic, Marija, 2017-05-09 TP53 binds the PTEN promoter TP53 binds the PTEN promoter PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers. TP53 (p53) binds to the p53-binding site at the PTEN promoter level (Stambolic et al. 2001). Authored: Orlic-Milacic, Marija, 2014-12-23 Reviewed: Hwang, Paul M, 2014-12-30 Reviewed: Kang, Ju-Gyeong, 2014-12-30 Reviewed: Wang, Ping-yuan, 2014-12-30 Reviewed: Inga, Alberto, 2016-02-04 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Salmena, Leonardo, 2016-08-11 Reviewed: Carracedo, Arkaitz, 2016-08-11 Reviewed: Leslie, Nicholas, 2016-09-30 Reviewed: Kriplani, Nisha, 2016-09-30 Edited: Orlic-Milacic, Marija, 2014-12-23 Reactome DB_ID: 3209194 1 TP53 Tetramer [nucleoplasm] TP53 Tetramer Reactome DB_ID: 69488 4 UniProt:P04637 TP53 TP53 TP53 P53 FUNCTION Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type (PubMed:11025664, PubMed:12524540, PubMed:12810724, PubMed:15186775, PubMed:15340061, PubMed:17317671, PubMed:17349958, PubMed:19556538, PubMed:20673990, PubMed:20959462, PubMed:22726440, PubMed:24051492, PubMed:9840937, PubMed:24652652). Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process (PubMed:11025664, PubMed:12524540, PubMed:12810724, PubMed:15186775, PubMed:15340061, PubMed:17317671, PubMed:17349958, PubMed:19556538, PubMed:20673990, PubMed:20959462, PubMed:22726440, PubMed:24051492, PubMed:9840937, PubMed:24652652). One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (PubMed:12524540). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (PubMed:12524540). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2 (PubMed:24051492).SUBUNIT Forms homodimers and homotetramers (PubMed:19011621). Binds DNA as a homotetramer. Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1 (By similarity). Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. May interact with HCV core protein. Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity (By similarity). Interacts with ARMC10, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F1. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-15 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-382) with L3MBTL1. Isoform 1 interacts with isoform 2 and with isoform 4. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with PPIF; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by cyclosporin A (CsA). Interacts with SNAI1; the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts with KAT6A. Interacts with UBC9. Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-binding domain) with ZNF385A; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest. Interacts with ANKRD2. Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination. Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus). Interacts with MORC3 (PubMed:17332504). Interacts (via C-terminus) with POU4F2 isoform 1 (via C-terminus) (PubMed:17145718). Interacts (via oligomerization region) with NOP53; the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of TP53 (PubMed:22522597). Interacts with AFG1L; mediates mitochondrial translocation of TP53 (PubMed:27323408). Interacts with UBD (PubMed:25422469). Interacts with TAF6 isoform 1 and isoform 4 (PubMed:20096117). Interacts with C10orf90/FATS; the interaction inhibits binding of TP53 and MDM2 (By similarity). Interacts with NUPR1; interaction is stress-dependent (PubMed:18690848). Forms a complex with EP300 and NUPR1; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A (PubMed:18690848). Interacts with PRMT5 in response to DNA damage; the interaction is TTC5/STRAP dependent (PubMed:19011621). Interacts with PPP1R13L (via SH3 domain and ANK repeats); the interaction inhibits pro-apoptotic activity of p53/TP53 (PubMed:12524540). Interacts with PPP1R13B/ASPP1 and TP53BP2/ASPP2; the interactions promotes pro-apoptotic activity (PubMed:12524540). When phosphorylated at Ser-15, interacts with DDX3X and gamma-tubulin (PubMed:28842590). Interacts with KAT7/HBO1; leading to inhibit histone acetyltransferase activity of KAT7/HBO1 (PubMed:17954561). Interacts (via N-terminus) with E3 ubiquitin-protein ligase MUL1; the interaction results in ubiquitination of cytoplasmic TP53 at Lys-24 and subsequent proteasomal degradation (PubMed:21597459). Interacts with S100A4; this interaction promotes TP53 degradation (PubMed:23752197, PubMed:32442400). Interacts with BANP (By similarity). Interacts with TTC5/STRAP; the interaction may result in increased mitochondrial-dependent apoptosis (PubMed:25168243). Interacts with NQO1; this interaction is NADH-dependent, stabilizes TP53 in response to oxidative stress and protects it from ubiquitin-independent degradation by the 20S proteasome.SUBUNIT (Microbial infection) Interacts with cancer-associated/HPV E6 viral proteins leading to ubiquitination and degradation of TP53 giving a possible model for cell growth regulation. This complex formation requires an additional factor, E6-AP, which stably associates with TP53 in the presence of E6.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123.SUBUNIT (Microbial infection) Interacts (via N-terminus) with human adenovirus 5 E1B-55K protein; this interaction leads to the inhibition of TP53 function and/or its degradation.SUBUNIT (Microbial infection) Interacts with Kaposi's sarcoma-associated herpesvirus/HHV-8 protein ORF45; this interaction results in the cytoplasmic localization of TP53 thereby decreasing its transcriptional activity.TISSUE SPECIFICITY Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine.INDUCTION Up-regulated in response to DNA damage. Isoform 2 is not induced in tumor cells in response to stress.DOMAIN The nuclear export signal acts as a transcriptional repression domain. The TADI and TADII motifs (residues 17 to 25 and 48 to 56) correspond both to 9aaTAD motifs which are transactivation domains present in a large number of yeast and animal transcription factors.PTM Acetylation of Lys-382 by CREBBP enhances transcriptional activity (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171). Acetylation of Lys-382 by EP300 (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171). Deacetylation of Lys-382 by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171). Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171). Acetylation at Lys-381 increases stability (PubMed:29474172). Deacetylation at Lys-381 by SIRT6 decreases its stability, thereby regulating cell senescence (PubMed:29474172).PTM Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylated by HIPK1 (By similarity). Phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-18 by VRK1. Phosphorylated on Ser-20 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-20 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Phosphorylated on Thr-55 by TAF1, which promotes MDM2-mediated degradation. Phosphorylated on Ser-33 by CDK7 in a CAK complex in response to DNA damage. Phosphorylated on Ser-46 by HIPK2 upon UV irradiation. Phosphorylation on Ser-46 is required for acetylation by CREBBP. Phosphorylated on Ser-392 following UV but not gamma irradiation. Phosphorylated by NUAK1 at Ser-15 and Ser-392; was initially thought to be mediated by STK11/LKB1 but it was later shown that it is indirect and that STK11/LKB1-dependent phosphorylation is probably mediated by downstream NUAK1 (PubMed:21317932). It is unclear whether AMP directly mediates phosphorylation at Ser-15. Phosphorylated on Thr-18 by isoform 1 and isoform 2 of VRK2. Phosphorylation on Thr-18 by isoform 2 of VRK2 results in a reduction in ubiquitination by MDM2 and an increase in acetylation by EP300. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-15, Ser-33 and Ser-46, leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes. Phosphorylated by DYRK2 at Ser-46 in response to genotoxic stress. Phosphorylated at Ser-315 and Ser-392 by CDK2 in response to DNA-damage. Phosphorylation at Ser-15 is required for interaction with DDX3X and gamma-tubulin (PubMed:28842590).PTM Dephosphorylated by PP2A-PPP2R5C holoenzyme at Thr-55. SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A.PTM May be O-glycosylated in the C-terminal basic region. Studied in EB-1 cell line.PTM Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation (PubMed:10722742, PubMed:12810724, PubMed:15340061, PubMed:17170702, PubMed:19880522). Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:10722742, PubMed:12810724, PubMed:20173098). Ubiquitinated by MKRN1 at Lys-291 and Lys-292, which leads to proteasomal degradation (PubMed:19536131). Deubiquitinated by USP10, leading to its stabilization (PubMed:20096447). Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation (PubMed:19556538). Ubiquitination by TOPORS induces degradation (PubMed:19473992). Deubiquitination by USP7, leading to stabilization (PubMed:15053880). Isoform 4 is monoubiquitinated in an MDM2-independent manner (PubMed:15340061). Ubiquitinated by COP1, which leads to proteasomal degradation (PubMed:19837670). Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2 (PubMed:25732823). Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (By similarity). Polyubiquitinated by MUL1 at Lys-24 which leads to proteasomal degradation (PubMed:21597459).PTM Monomethylated at Lys-372 by SETD7, leading to stabilization and increased transcriptional activation (PubMed:15525938, PubMed:16415881). Monomethylated at Lys-370 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity (PubMed:17108971). Lys-372 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-370 (PubMed:17108971). Dimethylated at Lys-373 by EHMT1 and EHMT2 (PubMed:20118233). Monomethylated at Lys-382 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity (PubMed:17707234). Dimethylation at Lys-370 and Lys-382 diminishes p53 ubiquitination, through stabilizing association with the methyl reader PHF20 (PubMed:22864287). Demethylation of dimethylated Lys-370 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation (PubMed:17805299). Monomethylated at Arg-333 and dimethylated at Arg-335 and Arg-337 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity (PubMed:19011621).PTM Sumoylated with SUMO1. Sumoylated at Lys-386 by UBC9.DISEASE TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.SIMILARITY Belongs to the p53 family.CAUTION Interaction with BANP was reported to enhance phosphorylation on Ser-15 upon ultraviolet irradiation (PubMed:15701641). However, the publication has been retracted due to image duplication and manipulation. Interaction with BANP has been confirmed in mouse studies (By similarity). Phosphorylation at Ser-15 has been confirmed by other studies (PubMed:10570149, PubMed:11554766, PubMed:16219768, PubMed:15866171, PubMed:17317671, PubMed:17954561, PubMed:20959462, PubMed:25772236). Its nuclear and cytoplasmic localization has been confirmed by other studies (PubMed:15340061, PubMed:17170702, PubMed:19011621, PubMed:21597459, PubMed:22726440, PubMed:17591690, PubMed:18206965). UniProt P04637 1 EQUAL 393 EQUAL Reactome Database ID Release 82 3209194 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3209194 Reactome R-HSA-3209194 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3209194.1 Reactome DB_ID: 5632949 1 ENSEMBL:ENSG00000171862 PTEN TEP1 PTEN MMAC1 ENSEMBL ENSG00000171862 Reactome DB_ID: 5632941 1 TP53 Tetramer:PTEN Gene [nucleoplasm] TP53 Tetramer:PTEN Gene Reactome DB_ID: 3209194 1 Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 5632941 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632941 Reactome R-HSA-5632941 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632941.1 Reactome Database ID Release 82 5632939 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632939 Reactome R-HSA-5632939 6 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632939.6 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 EGR1 binds the PTEN gene promoter EGR1 binds the PTEN gene promoter In response to UV-induced DNA damage, expresion levels of both EGR1 and PTEN increase. EGR1 binds directly to the EGR1 binding site GCGGCGGCG in the promoter region of PTEN to stimulate PTEN transcription (Virolle et al. 2001). Authored: Orlic-Milacic, Marija, 2015-10-29 Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 1031703 1 UniProt:P18146 EGR1 EGR1 EGR1 KROX24 ZNF225 FUNCTION Transcriptional regulator (PubMed:20121949). Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3'(EGR-site) in the promoter region of target genes (By similarity). Binds double-stranded target DNA, irrespective of the cytosine methylation status (PubMed:25258363, PubMed:25999311). Regulates the transcription of numerous target genes, and thereby plays an important role in regulating the response to growth factors, DNA damage, and ischemia. Plays a role in the regulation of cell survival, proliferation and cell death. Activates expression of p53/TP53 and TGFB1, and thereby helps prevent tumor formation. Required for normal progress through mitosis and normal proliferation of hepatocytes after partial hepatectomy. Mediates responses to ischemia and hypoxia; regulates the expression of proteins such as IL1B and CXCL2 that are involved in inflammatory processes and development of tissue damage after ischemia. Regulates biosynthesis of luteinizing hormone (LHB) in the pituitary (By similarity). Regulates the amplitude of the expression rhythms of clock genes: ARNTL/BMAL1, PER2 and NR1D1 in the liver via the activation of PER1 (clock repressor) transcription. Regulates the rhythmic expression of core-clock gene ARNTL/BMAL1 in the suprachiasmatic nucleus (SCN) (By similarity).SUBUNIT Interacts with SNAI1 and SP1 upon 12-O-tetradecanoylphorbol-13-acetate (TPA) induction.TISSUE SPECIFICITY Detected in neutrophils (at protein level).INDUCTION By growth factors.DOMAIN Binds to DNA motifs with the sequence 5'-GCG(T/G)GGGCG-3' via its C2H2-type zinc fingers (PubMed:25258363, PubMed:25999311). The first, most N-terminal zinc finger binds to the 3'-GCG motif, the middle zinc finger interacts with the central TGG motif, and the C-terminal zinc finger binds to the 5'-GCG motif. Binds double-stranded target DNA, irrespective of the cytosine methylation status. Has reduced affinity for target DNA where the cytosines have been oxidized to 5-hydroxymethylcytosine. Does not bind target DNA where the cytosines have been oxidized to 5-formylcytosine or 5-carboxylcytosine (PubMed:25258363).SIMILARITY Belongs to the EGR C2H2-type zinc-finger protein family. UniProt P18146 1 EQUAL 543 EQUAL Reactome DB_ID: 5632949 1 Reactome DB_ID: 8944084 1 EGR1:PTEN gene [nucleoplasm] EGR1:PTEN gene Reactome DB_ID: 1031703 1 1 EQUAL 543 EQUAL Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 8944084 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944084 Reactome R-HSA-8944084 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944084.1 Reactome Database ID Release 82 8944078 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944078 Reactome R-HSA-8944078 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944078.1 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 Activated PPARG binds PTEN gene promoter Activated PPARG binds PTEN gene promoter The nuclear receptor PPARG (PPARgamma), activated by ligand binding, binds to peroxisome proliferator response elements (PPREs) in the promoter of the PTEN gene to activate PTEN transcription. It has not been tested whether nuclear receptors that heterodimerize with PPARG are involved in transcriptional regulation of PTEN (Patel et al. 2001). Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-11-02 Reviewed: Leslie, Nicholas, 2016-09-30 Reviewed: Kriplani, Nisha, 2016-09-30 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 2026077 1 PPARG:Fatty Acid Ligand [nucleoplasm] PPARG:Fatty Acid Ligand Converted from EntitySet in Reactome Reactome DB_ID: 381235 2 Ligands of PPARG [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity RGZ [nucleoplasm] 9S-HODE [nucleoplasm] 13(S')-HODE [nucleoplasm] Actos [nucleoplasm] ChEBI 50122 ChEBI 34496 ChEBI 34154 ChEBI 8228 Reactome DB_ID: 446172 1 UniProt:P37231 PPARG PPARG PPARG NR1C3 FUNCTION Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated pro-inflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity).FUNCTION (Microbial infection) Upon treatment with M.tuberculosis or its lipoprotein LpqH, phosphorylation of MAPK p38 and IL-6 production are modulated, probably via this protein.ACTIVITY REGULATION PDPK1 activates its transcriptional activity independently of its kinase activity.SUBUNIT Interacts with FOXO1 (acetylated form) (By similarity). Heterodimer with other nuclear receptors, such as RXRA. The heterodimer with the retinoic acid receptor RXRA is called adipocyte-specific transcription factor ARF6. Interacts with NCOA6 coactivator, leading to a strong increase in transcription of target genes. Interacts with coactivator PPARBP, leading to a mild increase in transcription of target genes. Interacts with NOCA7 in a ligand-inducible manner. Interacts with NCOA1 and NCOA2 LXXLL motifs. Interacts with ASXL1, ASXL2, DNTTIP2, FAM120B, MAP2K1/MEK1, NR0B2, PDPK1, PRDM16, PRMT2 and TGFB1I1. Interacts (when activated by agonist) with PPP5C. Interacts with HELZ2 and THRAP3; the interaction stimulates the transcriptional activity of PPARG. Interacts with PER2, the interaction is ligand dependent and blocks PPARG recruitment to target promoters. Interacts with NOCT. Interacts with ACTN4. Interacts (when in the liganded conformation) with GPS2 (By similarity). Interacts with CRY1 and CRY2 in a ligand-dependent manner (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863).TISSUE SPECIFICITY Highest expression in adipose tissue. Lower in skeletal muscle, spleen, heart and liver. Also detectable in placenta, lung and ovary.INDUCTION (Microbial infection) Expression increases when incubated with M.tuberculosis or its lipoprotein LpqH; induction is TLR2-dependent (at protein level).DOMAIN The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.PTM O-GlcNAcylation at Thr-84 reduces transcriptional activity in adipocytes.PTM Phosphorylated in basal conditions and dephosphorylated when treated with the ligand. May be dephosphorylated by PPP5C. The phosphorylated form may be inactive and dephosphorylation at Ser-112 induces adipogenic activity (By similarity).POLYMORPHISM Genetic variations in PPARG define the body mass index quantitative trait locus 1 (BMIQ1) [MIM:606641]. The body max index (BMI) reflects the amount of fat, lean mass, and body build.POLYMORPHISM Genetic variations in PPARG influence the carotid intimal medial thickness (CIMT) [MIM:609338]. CIMT is a measure of atherosclerosis that is independently associated with traditional atherosclerotic cardiovascular disease risk factors and coronary atherosclerotic burden. 35 to 45% of the variability in multivariable-adjusted CIMT is explained by genetic factors.DISEASE Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer.SIMILARITY Belongs to the nuclear hormone receptor family. NR1 subfamily. UniProt P37231 1 EQUAL 505 EQUAL Reactome Database ID Release 82 2026077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2026077 Reactome R-HSA-2026077 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2026077.2 Reactome DB_ID: 5632949 1 Reactome DB_ID: 8944097 1 PPARG:Fatty Acid Ligand:PTEN gene [nucleoplasm] PPARG:Fatty Acid Ligand:PTEN gene Reactome DB_ID: 2026077 1 Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 8944097 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944097 Reactome R-HSA-8944097 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944097.1 Reactome Database ID Release 82 8944099 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944099 Reactome R-HSA-8944099 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944099.1 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 NR2E1 associated with transcription repressors binds PTEN promoter NR2E1 associated with transcription repressors binds PTEN promoter NR2E1 (TLX) associated with transcription repressors binds the evolutionarily conserved TLX consensus site in the PTEN promoter. NR2E1 inhibits PTEN transcription by associating with various transcriptional repressors, probably in a cell type or tissue specific manner. PTEN transcription is inhibited when NR2E1 forms a complex with ATN1 (atrophin-1) (Zhang et al. 2006, Yokoyama et al. 2008), KDM1A (LSD1) histone methyltransferase containing CoREST complex (Yokoyama et al. 2008), or histone deacetylases HDAC3, HDAC5 or HDAC7 (Sun et al. 2007). Authored: Orlic-Milacic, Marija, 2015-10-29 Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Reviewed: Leslie, Nicholas, 2016-09-30 Reviewed: Kriplani, Nisha, 2016-09-30 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 6807075 1 NR2E1:(CoREST complex,ATN1,HDAC3,HDAC5,HDAC7) [nucleoplasm] NR2E1:(CoREST complex,ATN1,HDAC3,HDAC5,HDAC7) Converted from EntitySet in Reactome Reactome DB_ID: 6808474 1 CoREST complex,ATN1,HDAC3,5,7 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity HDAC5 [nucleoplasm] HDAC7 [nucleoplasm] HDAC3 [nucleoplasm] UniProt Q9UQL6 UniProt Q8WUI4 UniProt O15379 Reactome DB_ID: 376207 1 UniProt:Q9Y466 NR2E1 NR2E1 TLX NR2E1 FUNCTION Orphan receptor that binds DNA as a monomer to hormone response elements (HRE) containing an extended core motif half-site sequence 5'-AAGGTCA-3' in which the 5' flanking nucleotides participate in determining receptor specificity (By similarity). May be required to pattern anterior brain differentiation. Involved in the regulation of retinal development and essential for vision. During retinogenesis, regulates PTEN-Cyclin D expression via binding to the promoter region of PTEN and suppressing its activity (By similarity). May be involved in retinoic acid receptor (RAR) regulation in retinal cells.SUBUNIT Monomer. Interacts with ATN1; the interaction represses the transcription.TISSUE SPECIFICITY Brain specific. Present in all brain sections tested, highest levels in the caudate nucleus and hippocampus, weakest levels in the thalamus.SIMILARITY Belongs to the nuclear hormone receptor family. NR2 subfamily. UniProt Q9Y466 1 EQUAL 385 EQUAL Reactome Database ID Release 82 6807075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6807075 Reactome R-HSA-6807075 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6807075.1 Reactome DB_ID: 5632949 1 Reactome DB_ID: 6807085 1 NR2E1:(CoREST complex,ATN1,HDAC3,HDAC5,HDAC7):PTEN Gene [nucleoplasm] NR2E1:(CoREST complex,ATN1,HDAC3,HDAC5,HDAC7):PTEN Gene Reactome DB_ID: 6807075 1 Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 6807085 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6807085 Reactome R-HSA-6807085 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6807085.1 Reactome Database ID Release 82 6807077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6807077 Reactome R-HSA-6807077 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6807077.1 18391013 Pubmed 2008 Transrepressive function of TLX requires the histone demethylase LSD1 Yokoyama, Atsushi Takezawa, Shinichiro Schüle, Roland Kitagawa, Hirochika Kato, Shigeaki Mol. Cell. Biol. 28:3995-4003 17873065 Pubmed 2007 Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation Sun, Guoqiang Yu, Ruth T Evans, Ronald M Shi, Yanhong Proc. Natl. Acad. Sci. U.S.A. 104:15282-7 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 SALL4 binds the PTEN gene promoter SALL4 binds the PTEN gene promoter The transcription factor SALL4 binds the promoter of the PTEN gene (Yang et al. 2008, Lu et al. 2009). Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 452644 1 UniProt:Q9UJQ4 SALL4 SALL4 SALL4 ZNF797 FUNCTION Transcription factor with a key role in the maintenance and self-renewal of embryonic and hematopoietic stem cells.SUBUNIT Interacts with POU5F1/OCT4 (PubMed:23012367). Interacts with NANOG (By similarity). Interacts with BEND3 (PubMed:21914818). Interacts with NSD2 (via PHD-type zinc fingers 1, 2 and 3) (By similarity).TISSUE SPECIFICITY Expressed in testis. Constitutively expressed in acute myeloid leukemia (AML).PTM Isoform SALL4B exists primarily as a ubiquitinated form.PTM Sumoylation with both SUMO1 and SUMO2 regulates the stability, subcellular localization, transcriptional activity, and may reduce interaction with POU5F1/OCT4.SIMILARITY Belongs to the sal C2H2-type zinc-finger protein family. UniProt Q9UJQ4 1 EQUAL 1053 EQUAL Reactome DB_ID: 5632949 1 Reactome DB_ID: 8943729 1 SALL4:PTEN gene [nucleoplasm] SALL4:PTEN gene Reactome DB_ID: 452644 1 1 EQUAL 1053 EQUAL Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 8943729 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943729 Reactome R-HSA-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-HSA-8943729.1 Reactome Database ID Release 82 8943728 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943728 Reactome R-HSA-8943728 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8943728.1 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 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 SALL4 recruits NuRD to PTEN gene SALL4 recruits NuRD to PTEN gene 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). Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-10-29 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 8943729 1 Reactome DB_ID: 4657018 1 NuRD complex [nucleoplasm] NuRD complex Reactome DB_ID: 4657010 1 UniProt:O95983 MBD3 MBD3 MBD3 FUNCTION Acts as transcriptional repressor and plays a role in gene silencing. Does not bind to DNA by itself (PubMed:12124384). Binds to DNA with a preference for sites containing methylated CpG dinucleotides (in vitro). Binds to a lesser degree DNA containing unmethylated CpG dinucleotides (PubMed:24307175). Recruits histone deacetylases and DNA methyltransferases.SUBUNIT Heterodimer with MBD2 (PubMed:10947852). Part of the NuRD and the MeCP1 complex (PubMed:12124384, PubMed:11756549, PubMed:15454082). Interacts with BCL6, HDAC1, MTA2, DNMT1, p66-alpha and p66-beta (PubMed:11102443, PubMed:12124384, PubMed:12183469, PubMed:11756549, PubMed:15454082). Does not interact with PWWP2A and PWWP2B (By similarity). UniProt O95983 1 EQUAL 291 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 4657019 1 MTA1, MTA2, MTA3 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MTA1 [nucleoplasm] MTA3 [nucleoplasm] MTA2 [nucleoplasm] UniProt Q13330 UniProt Q9BTC8 UniProt O94776 Converted from EntitySet in Reactome Reactome DB_ID: 4657021 1 Mi-2 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CHD4 [nucleoplasm] CHD3 [nucleoplasm] UniProt Q14839 UniProt Q12873 Reactome DB_ID: 4657004 1 HDAC1:HDAC2 [nucleoplasm] HDAC1:HDAC2 Reactome DB_ID: 205021 1 UniProt:Q13547 HDAC1 HDAC1 HDAC1 RPD3L1 FUNCTION Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:16762839, PubMed:17704056, PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:16762839, PubMed:17704056). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:16762839, PubMed:17704056). Also functions as deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3 and TSHZ3 (PubMed:12837748, PubMed:16478997, PubMed:17996965, PubMed:19343227). Deacetylates SP proteins, SP1 and SP3, and regulates their function (PubMed:12837748, PubMed:16478997). Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons (PubMed:19081374). Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation (PubMed:19081374). Deacetylates TSHZ3 and regulates its transcriptional repressor activity (PubMed:19343227). Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B (PubMed:17000776). Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity (PubMed:17996965). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (By similarity). Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer (By similarity). Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation (By similarity). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones (PubMed:28497810).SUBUNIT Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7 (PubMed:12493763, PubMed:12724404, PubMed:19061646). The core complex associates with MTA2, MBD2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex (PubMed:11102443). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST and PHF21A/BHC80 (PubMed:12493763). The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (PubMed:12493763). Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3/SAP45, ARID4B/SAP180, HDAC1 and HDAC2 (PubMed:12724404). Found in a trimeric complex with APBB1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3 (PubMed:19343227). Interacts with TSHZ3 (via N-terminus); the interaction is direct (PubMed:19343227). Component of a RCOR/GFI/KDM1A/HDAC complex (By similarity). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (PubMed:17704056). Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2 (PubMed:19061646). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A (By similarity). Associates with the 9-1-1 complex; interacts with HUS1 (PubMed:10846170). Found in a complex with DNMT3A and HDAC7 (By similarity). Interacts with the non-histone region of MACROH2A1 (By similarity). Interacts with TRIM28; the interaction recruits HDAC1 to E2F1 and inhibits its acetylation (PubMed:17704056). Interacts with SP1; the interaction deacetylates SP1 and regulates its transcriptional activity (PubMed:16478997). Interacts with SP3; the interaction deacetylates SP3 and regulates its transcriptional activity (PubMed:12837748, PubMed:17548428). In vitro, C(18) ceramides increase this interaction and the subsequent SP3 deacetylation and SP3-mediated repression of the TERT promoter (PubMed:12837748, PubMed:17548428). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (PubMed:14633989). Interacts with C10orf90/FATS (via its N-terminal); the interaction prevents binding of HDAC1 to CDKN1A/p21 and facilitates the acetylation and stabilization of CDKN1A/p21 (By similarity). Interacts with CDKN1A/p21 (By similarity). Interacts with CDK5 complexed to CDK5R1 (p25) (By similarity). Interacts directly with GFI1 and GFI1B (By similarity). Interacts with NR1D2 (via C-terminus) (PubMed:17996965). Interacts with TSC22D3 isoform 1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity (By similarity). Interacts with BAZ2A/TIP5, BANP, BCL6, BCOR, BHLHE40/DEC1, BRMS1, BRMS1L, CBFA2T3, CHFR, CIART, CRY1, DAXX, DDIT3/CHOP, DDX5, DNMT1, E4F1, EP300, HCFC1, HDAC9, INSM1, NFE4, NR4A2/NURR1, MIER1, KDM4A, KDM5B, KLF1, MINT, NRIP1, PCAF, PHB2, PRDM6, PRDM16, RB1, RERE, SAMSN1, SAP30L, SETDB1, SMAD3, SMARCAD1, SMARCA4/BRG1, SMYD2, SUV39H1, TGIF, TGIF2, TRAF6, UHRF1, UHRF2, ZMYND15, ZNF431 and ZNF541 (PubMed:10669754, PubMed:17369852, PubMed:19081374, PubMed:19182791, PubMed:21549307, PubMed:11331609, PubMed:11006275, PubMed:10846170, PubMed:12730668, PubMed:18093978, PubMed:11533236, PubMed:10898795, PubMed:10655483, PubMed:16569215, PubMed:16820529, PubMed:17872950, PubMed:12670868, PubMed:21829689, PubMed:10487760, PubMed:11427533, PubMed:19049980, PubMed:15273251, PubMed:15361834, PubMed:17373667, PubMed:16166625, PubMed:15454082, PubMed:17000776, PubMed:15927959, PubMed:15451426, PubMed:12482978). Interacts with KDM5A; this interaction impairs histone deacetylation (By similarity). Interacts with DNTTIP1 (PubMed:25653165). Identified in a histone deacetylase complex that contains DNTTIP1, HDAC1 and MIDEAS; this complex assembles into a tetramer that contains four copies of each protein chain (PubMed:25653165). Interacts with CCAR2 (PubMed:21030595). Interacts with PPHLN1 (PubMed:17963697). Found in a complex with YY1, SIN3A and GON4L (By similarity). Interacts with CHD4 (PubMed:27616479). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (By similarity). Interacts with SIN3A (By similarity). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts with ZBTB7A (PubMed:25514493). Interacts with SMAD4; positively regulated by ZBTB7A (PubMed:25514493). Interacts with PACS2 (PubMed:29656858). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC2 (PubMed:19433865). Interacts with ZNF638 (PubMed:30487602). Interacts with SPHK2 (PubMed:19729656). Interacts with ERCC6 (PubMed:26030138). Interacts with NSD2 (By similarity). Interacts with SMYD4 (via MYND-type zinc finger) (PubMed:30110327). Interacts with PWWP2A in a MTA1-dependent manner (By similarity). Interacts with PWWP2B (By similarity). Interacts with ZNF516 and BRCC3; these interactions are enhanced in the presence of PWWP2B (By similarity). Interacts with SANBR (via the BTB domain) (By similarity).SUBUNIT (Microbial infection) Interacts with SV40 large T antigen.TISSUE SPECIFICITY Ubiquitous, with higher levels in heart, pancreas and testis, and lower levels in kidney and brain.PTM Sumoylated on Lys-444 and Lys-476; which promotes enzymatic activity. Desumoylated by SENP1.PTM Phosphorylation on Ser-421 and Ser-423 promotes enzymatic activity and interactions with NuRD and SIN3 complexes. Phosphorylated by CDK5.PTM Ubiquitinated by CHFR, leading to its degradation by the proteasome. Ubiquitinated by KCTD11, leading to proteasomal degradation.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt Q13547 1 EQUAL 482 EQUAL Reactome DB_ID: 205135 1 UniProt:Q92769 HDAC2 HDAC2 HDAC2 FUNCTION Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (By similarity). Histone deacetylases act via the formation of large multiprotein complexes (By similarity). Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR (PubMed:12724404). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (By similarity). Also deacetylates non-histone targets: deacetylates TSHZ3, thereby regulating its transcriptional repressor activity (PubMed:19343227). May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation (By similarity). Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A (PubMed:21965678). In addition to protein deacetylase activity, also acts as protein-lysine deacylase by recognizing other acyl groups: catalyzes removal of (2E)-butenoyl (crotonyl) and 2-hydroxyisobutanoyl (2-hydroxyisobutyryl) acyl groups from lysine residues, leading to protein decrotonylation and de-2-hydroxyisobutyrylation, respectively (PubMed:28497810, PubMed:29192674).SUBUNIT Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7 (PubMed:10904264). The core complex associates with MTA2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex (PubMed:10904264). Component of a RCOR/GFI/KDM1A/HDAC complex (By similarity). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B, KDM1A, RCOR1 and PHF21A (PubMed:12493763). The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (PubMed:12493763). Part of a complex containing the core histones H2A, H2B, H3 and H4, DEK and unphosphorylated DAXX (PubMed:12140263). Part of a complex containing ATR and CHD4 (PubMed:10545197). Forms a heterologous complex at least with YY1 (PubMed:8917507). Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1 (PubMed:10888872). Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3, ARID4B, HDAC1 and HDAC2 (PubMed:12724404). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (PubMed:10904264). Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2 (PubMed:19061646). Component of a histone deacetylase complex containing DNTTIP1, ZNF541, HDAC1 and HDAC2 (PubMed:21573134). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC1 (PubMed:19433865). Interacts with SPHK2 (PubMed:19729656). Interacts directly with GFI1 and GFI1B (By similarity). Interacts with SNW1, HDAC7, PRDM6, SAP30, SETDB1 and SUV39H1 (PubMed:10644367). Interacts with the MACROH2A1 (via the non-histone region) (By similarity). Interacts with ATR, CBFA2T3, DNMT1, SMARCAD1, MINT, HDAC10, HCFC1, NRIP1, KDM4A and PELP1 (PubMed:15927959, PubMed:15456770, PubMed:15060175, PubMed:11331609, PubMed:21549307, PubMed:12670868, PubMed:11533236, PubMed:11739383, PubMed:10888872). Interacts with CHFR and SAP30L (PubMed:19182791, PubMed:16820529). Interacts (CK2 phosphorylated form) with SP3 (PubMed:12176973). Interacts with TSHZ3 (via its N-terminus) (PubMed:19343227). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (PubMed:14633989). Interacts with PIMREG (PubMed:18757745). Interacts with BCL6 (non-acetylated form) (PubMed:18212045, PubMed:12402037). Interacts with CRY1, INSM1 and ZNF431 (By similarity). Interacts with NACC2 (PubMed:22926524). Interacts with MTA1, with a preference for sumoylated MTA1 (PubMed:21965678, PubMed:24970816). Interacts with SIX3 (By similarity). Interacts with BEND3 (PubMed:21914818). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553). Interacts with PWWP2B (By similarity).TISSUE SPECIFICITY Widely expressed; lower levels in brain and lung.PTM S-nitrosylated by GAPDH. In neurons, S-nitrosylation at Cys-262 and Cys-274 does not affect enzyme activity, but induces HDAC2 release from chromatin. This in turn increases acetylation of histones surrounding neurotrophin-dependent gene promoters and promotes their transcription. In embryonic cortical neurons, S-Nitrosylation regulates dendritic growth and branching.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt Q92769 1 EQUAL 488 EQUAL Reactome Database ID Release 82 4657004 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4657004 Reactome R-HSA-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-HSA-4657004.1 Reactome DB_ID: 212223 1 UniProt:Q09028 RBBP4 RBBP4 RBBP4 RBAP48 FUNCTION Core histone-binding subunit that may target chromatin assembly factors, chromatin remodeling factors and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the chromatin assembly factor 1 (CAF-1) complex, which is required for chromatin assembly following DNA replication and DNA repair; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; the PRC2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex.SUBUNIT Interacts with SUV39H1 and HDAC7 (By similarity). Binds directly to helix 1 of the histone fold of histone H4, a region that is not accessible when H4 is in chromatin (PubMed:8858152, PubMed:9427644). Subunit of the chromatin assembly factor 1 (CAF-1) complex, which is composed of RBBP4, CHAF1B and CHAF1A (PubMed:8858152). Subunit of the core histone deacetylase (HDAC) complex, which is composed of HDAC1, HDAC2, RBBP4 and RBBP7 (PubMed:9150135). The core HDAC complex associates with SIN3A, ARID4B/SAP180, SAP18, SAP30, SAP130, SUDS3/SAP45 and possibly ARID4A/RBP1 and ING1 to form the SIN3 HDAC complex (PubMed:9150135, PubMed:9651585, PubMed:11118440, PubMed:11784859). The core HDAC complex may also associate with MTA2, MBD3, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylase complex (the NuRD complex) (PubMed:9790534, PubMed:10444591, PubMed:11102443). The NuRD complex may also interact with MBD3L1 and MBD3L2 (PubMed:15456747, PubMed:15701600). Interacts with MTA1 (PubMed:12920132). Component of the PRC2 complex, which consists of the core subunits EED, EZH1 or EZH2, SUZ12, and RBBP4, and various combinations of accessory subunits including AEBP2, JARID2, PHF19, MTF2 and EPOP (PubMed:12435631, PubMed:12351676, PubMed:29499137, PubMed:31959557). Forms a monomeric PRC2.2 (class 2) complex consisting of at least SUZ12, RBBP4, AEBP2 and JARID2 (PubMed:29499137). Forms a dimeric PRC2.1 (class 1, PRC-PCL) complex consisting of at least SUZ12, RBBP4, and PHF19; PHF19 stabilizes the dimeric structure which enhances PRC2 interaction with chromatin (PubMed:31959557). Component of the NURF-1 ISWI chromatin remodeling complex (also called the nucleosome-remodeling factor (NURF) complex) at least composed of SMARCA1 (isoform 2), BPTF, RBBP4 and RBBP7 (PubMed:14609955, PubMed:15310751). Within the complex interacts with isoform 2 of SMARCA1 (PubMed:14609955, PubMed:15310751). Component of the BPFT-SMARCA1 complex at least composed of SMARCA1 (isoform 1), BPFT, RBBP4 and RBBP7; the complex is catalytically inactive and does not remodel chromatin (PubMed:15310751). Within the complex interacts with isoform 1 of SMARCA1 (PubMed:15310751). Interacts with the ISWI chromatin remodeling complex component SMARCA5; the interaction is direct (PubMed:12198550). Interacts with the viral protein-binding domain of the retinoblastoma protein (RB1) (PubMed:7503932, PubMed:10734134). Interacts with SPEN/MINT (PubMed:11331609). Interacts with BRCA1 (PubMed:10220405). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP (PubMed:10866654). Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2 (PubMed:17671431, PubMed:17531812). The complex exists in quiescent cells where it represses cell cycle-dependent genes (PubMed:17671431, PubMed:17531812). It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2 (PubMed:17671431, PubMed:17531812). Interacts with PHF6 (PubMed:24554700). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (By similarity). Interacts with ERCC6 (PubMed:26030138). Interacts with ZNF827; the interaction is direct and recruits RBBP4 to telomeres (PubMed:30045876). Interacts with ARMC12 (via ARM domains) (PubMed:30026490). Interacts with PWWP2B (By similarity).TISSUE SPECIFICITY Expressed in neuroblastoma cells.SIMILARITY Belongs to the WD repeat RBAP46/RBAP48/MSI1 family. UniProt Q09028 2 EQUAL 425 EQUAL Reactome DB_ID: 212227 1 UniProt:Q16576 RBBP7 RBBP7 RBBP7 RBAP46 FUNCTION Core histone-binding subunit that may target chromatin remodeling factors, histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the type B histone acetyltransferase (HAT) complex, which is required for chromatin assembly following DNA replication; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; and the PRC2/EED-EZH2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex.SUBUNIT Binds directly to helix 1 of the histone fold of histone H4, a region that is not accessible when H4 is in chromatin (PubMed:18571423). Subunit of the type B histone acetyltransferase (HAT) complex, composed of RBBP7 and HAT1. Subunit of the core histone deacetylase (HDAC) complex, which is composed of HDAC1, HDAC2, RBBP4 and RBBP7. The core HDAC complex associates with SIN3A, ARID4B/SAP180, SAP18, SAP30, SAP130, SUDS3/SAP45 and possibly ARID4A/RBP1 and ING1 to form the SIN3 HDAC complex. The core HDAC complex may also associate with MTA2, MBD3, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylase complex (the NuRD complex). The NuRD complex may also interact with MBD3L1 and MBD3L2. Interacts with MTA1. Subunit of the PRC2/EED-EZH2 complex, which is composed of at least EED, EZH2, RBBP4, RBBP7 and SUZ12 (PubMed:12435631). The PRC2/EED-EZH2 complex may also associate with HDAC1. Component of the NURF-1 ISWI chromatin remodeling complex (also called the nucleosome-remodeling factor (NURF) complex) at least composed of SMARCA1 (isoform 2), BPTF, RBBP4 and RBBP7 (PubMed:14609955, PubMed:15310751). Within the complex interacts with isoform 2 of SMARCA1 (PubMed:14609955, PubMed:15310751). Component of the BPFT-SMARCA1 complex at least composed of SMARCA1 (isoform 1), BPFT, RBBP4 and RBBP7; the complex is catalytically inactive and does not remodel chromatin (PubMed:15310751). Within the complex interacts with isoform 1 of SMARCA1 (PubMed:15310751). Interacts with the viral protein-binding domain of the retinoblastoma protein (RB1) (PubMed:7503932, PubMed:10220405). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP. Interacts with BRCA1, HDAC7 and SUV39H1. Interacts with CENPA (PubMed:25556658). Interacts with PWWP2B (By similarity).SIMILARITY Belongs to the WD repeat RBAP46/RBAP48/MSI1 family. UniProt Q16576 2 EQUAL 425 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 4657014 1 (GATAD2A, GATAD2B) [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 4657018 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4657018 Reactome R-HSA-4657018 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4657018.2 Reactome DB_ID: 8943781 1 SALL4:NuRD:PTEN gene [nucleoplasm] SALL4:NuRD:PTEN gene Reactome DB_ID: 8943778 1 SALL4:NuRD [nucleoplasm] SALL4:NuRD Reactome DB_ID: 452644 1 1 EQUAL 1053 EQUAL Reactome DB_ID: 4657018 1 Reactome Database ID Release 82 8943778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943778 Reactome R-HSA-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-HSA-8943778.1 Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 8943781 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943781 Reactome R-HSA-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-HSA-8943781.1 Reactome Database ID Release 82 8943780 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943780 Reactome R-HSA-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-HSA-8943780.1 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 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 MECOM (EVI1) binds the PTEN gene promoter MECOM (EVI1) binds the PTEN gene promoter The transcription factor MECOM (EVI1) binds the promoter of the PTEN gene (Yoshimi et al. 2011). Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-10-30 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 8943897 1 UniProt:Q03112 MECOM MECOM MDS1 MECOM PRDM3 EVI1 DOMAIN Both zinc finger regions are required for the transcriptional activation of PBX1.PTM Phosphorylated.PTM May be acetylated by CREBBP and KAT2B.DISEASE A chromosomal aberration involving EVI1 is a cause of chronic myelogenous leukemia (CML). Translocation t(3;21)(q26;q22) with RUNX1/AML1.DISEASE A chromosomal aberration involving MDS1 is found in a form of acute myeloid leukemia (AML). Translocation t(3;21) with AML1. UniProt Q03112 1 EQUAL 1051 EQUAL Reactome DB_ID: 5632949 1 Reactome DB_ID: 8943810 1 MECOM:PTEN gene [nucleoplasm] MECOM:PTEN gene Reactome DB_ID: 8943897 1 1 EQUAL 1051 EQUAL Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 8943810 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943810 Reactome R-HSA-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-HSA-8943810.1 Reactome Database ID Release 82 8943811 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943811 Reactome R-HSA-8943811 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8943811.1 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 MECOM (EVI1) recruits polycomb repressor complexes (PRCs) to the PTEN gene promoter MECOM (EVI1) recruits polycomb repressor complexes (PRCs) to the PTEN gene promoter 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. Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-10-30 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 8943810 1 Converted from EntitySet in Reactome Reactome DB_ID: 8943822 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: 8943821 1 MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene Reactome DB_ID: 8943820 1 MECOM:(PRC1.4,PRC2 (EZH2) core) [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core) Converted from EntitySet in Reactome Reactome DB_ID: 8943822 1 Reactome DB_ID: 8943897 1 1 EQUAL 1051 EQUAL Reactome Database ID Release 82 8943820 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943820 Reactome R-HSA-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-HSA-8943820.1 Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 8943821 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943821 Reactome R-HSA-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-HSA-8943821.1 Reactome Database ID Release 82 8943817 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943817 Reactome R-HSA-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-HSA-8943817.1 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 SNAI1,SNAI2 bind the PTEN gene promoter SNAI1,SNAI2 bind the PTEN gene promoter The transcriptional repressor SNAI1 (Snail1) binds the promoter of the PTEN gene. Binding of SNAI1 to the PTEN promoter increases in response to ionizing radiation and interferes with binding of TP53 to the PTEN promoter. Phosphorylation of SNAI1 at serine residue S246 may be required for SNAI1-mediated repression of PTEN transcription (Escriva et al. 2008). Another Slug/Snail family member SNAI2 (SLUG) can also bind to the PTEN gene promoter to repress PTEN transcription (Uygur et al. 2015). Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-11-01 Edited: Orlic-Milacic, Marija, 2017-05-09 Converted from EntitySet in Reactome Reactome DB_ID: 8944073 1 SNAI1,SNAI2 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity SNAI2 [nucleoplasm] SNAI1 [nucleoplasm] UniProt O43623 UniProt O95863 Reactome DB_ID: 5632949 1 Reactome DB_ID: 8944024 1 SNAI1,SNAI2:PTEN gene [nucleoplasm] SNAI1,SNAI2:PTEN gene Converted from EntitySet in Reactome Reactome DB_ID: 8944073 1 Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 8944024 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944024 Reactome R-HSA-8944024 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944024.1 Reactome Database ID Release 82 8944026 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944026 Reactome R-HSA-8944026 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944026.1 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 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 JUN binds the PTEN gene promoter JUN binds the PTEN gene promoter The transcription factor JUN binds the AP-1 element in the PTEN gene promoter (Hettinger et al. 2007) and represses PTEN gene transcription. RAS/RAF/MAPK signaling positively affects JUN-mediated inhibition of PTEN transcription, but the mechanism is not known. The JUN partner FOS is not needed for JUN-mediated downregulation of PTEN (Vasudevan et al. 2007). Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-11-01 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 450250 1 UniProt:P05412 JUN JUN JUN FUNCTION Transcription factor that recognizes and binds to the AP-1 consensus motif 5'-TGA[GC]TCA-3' (PubMed:10995748, PubMed:22083952). Heterodimerizes with proteins of the FOS family to form an AP-1 transcription complex, thereby enhancing its DNA binding activity to the AP-1 consensus sequence 5'-TGA[GC]TCA-3' and enhancing its transcriptional activity (By similarity). Together with FOSB, plays a role in activation-induced cell death of T cells by binding to the AP-1 promoter site of FASLG/CD95L, and inducing its transcription in response to activation of the TCR/CD3 signaling pathway (PubMed:12618758). Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation (PubMed:17210646). Involved in activated KRAS-mediated transcriptional activation of USP28 in colorectal cancer (CRC) cells (PubMed:24623306). Binds to the USP28 promoter in colorectal cancer (CRC) cells (PubMed:24623306).SUBUNIT Heterodimer with either BATF3 or ATF7 (PubMed:10376527, PubMed:12087103, PubMed:15467742). Heterodimer with FOS (By similarity). Heterodimer with FOSB isoform 1 and 2 (By similarity). Component of an AP-1 transcription factor complex composed of JUN-FOS heterodimers (By similarity). As part of the AP-1 transcription factor complex, forms heterodimers with FOSB, thereby binding to the AP-1 consensus sequence and stimulating transcription (By similarity). Interacts with FOS and FOSB isoform 1 and 2 (By similarity). The ATF7/JUN heterodimer is essential for ATF7 transactivation activity (PubMed:10376527). Interacts with DSIPI; the interaction inhibits the binding of active AP1 to its target DNA (By similarity). Interacts with HIVEP3 and MYBBP1A (By similarity). Interacts with SP1, SPIB and TCF20 (PubMed:10196196, PubMed:16478997, PubMed:8663478). Interacts with COPS5; the interaction leads indirectly to its phosphorylation (PubMed:8837781). Component of the SMAD3/SMAD4/JUN/FOS/complex which forms at the AP1 promoter site (PubMed:10995748). The SMAD3/SMAD4 heterodimer acts synergistically with the JUN/FOS heterodimer to activate transcription in response to TGF-beta (PubMed:9732876). Interacts (via its basic DNA binding and leucine zipper domains) with SMAD3 (via an N-terminal domain); the interaction is required for TGF-beta-mediated transactivation of the SMAD3/SMAD4/JUN/FOS/complex (PubMed:10995748). Interacts with methylated RNF187 (PubMed:20852630, PubMed:23624934). Binds to HIPK3. Interacts (when phosphorylated) with FBXW7 (PubMed:14739463). Found in a complex with PRR7 and FBXW7 (PubMed:27458189). Interacts with PRR7 and FBXW7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (PubMed:27458189). Interacts with RBM39 (By similarity). Interacts with PAGE4 (PubMed:24263171, PubMed:24559171, PubMed:26242913).TISSUE SPECIFICITY Expressed in the developing and adult prostate and prostate cancer cells.PTM Ubiquitinated by the SCF(FBXW7), leading to its degradation (PubMed:14739463, PubMed:27458189). Ubiquitination takes place following phosphorylation, that promotes interaction with FBXW7 (PubMed:14739463).PTM Phosphorylated by CaMK4 and PRKDC; phosphorylation enhances the transcriptional activity. Phosphorylated by HIPK3. Phosphorylated by DYRK2 at Ser-243; this primes the protein for subsequent phosphorylation by GSK3B at Thr-239. Phosphorylated at Thr-239, Ser-243 and Ser-249 by GSK3B; phosphorylation reduces its ability to bind DNA. Phosphorylated by PAK2 at Thr-2, Thr-8, Thr-89, Thr-93 and Thr-286 thereby promoting JUN-mediated cell proliferation and transformation. Phosphorylated by PLK3 following hypoxia or UV irradiation, leading to increase DNA-binding activity.PTM Acetylated at Lys-271 by EP300.SIMILARITY Belongs to the bZIP family. Jun subfamily. UniProt P05412 1 EQUAL 331 EQUAL Reactome DB_ID: 5632949 1 Reactome DB_ID: 8944060 1 JUN:PTEN gene [nucleoplasm] JUN:PTEN gene Reactome DB_ID: 450250 1 1 EQUAL 331 EQUAL Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 8944060 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944060 Reactome R-HSA-8944060 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944060.1 Reactome Database ID Release 82 8944047 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944047 Reactome R-HSA-8944047 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944047.3 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 16676006 Pubmed 2007 c-Jun promotes cellular survival by suppression of PTEN Hettinger, K Vikhanskaya, F Poh, M K Lee, M K de Belle, I Zhang, J-T Reddy, S A G Sabapathy, K Cell Death Differ. 14:218-29 ACTIVATION Reactome Database ID Release 82 8944062 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944062 Reactome R-HSA-8944062 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944062.1 Converted from EntitySet in Reactome Reactome DB_ID: 1268261 p-T69,T71-ATF2 binds PTEN gene promoter p-T69,T71-ATF2 binds PTEN gene promoter The transcription factor ATF2, activated downstream of stress signaling by p38 MAPKs, binds to ATF response elements in the PTEN gene promoter to activate PTEN transcription. It has not been examined whether ATF2 heterodimerization partners are involved in ATF2-mediated up-regulation of PTEN (Shen et al. 2006). Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-11-03 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 450243 1 UniProt:P15336 ATF2 ATF2 CREB2 ATF2 CREBP1 FUNCTION Transcriptional activator which regulates the transcription of various genes, including those involved in anti-apoptosis, cell growth, and DNA damage response. Dependent on its binding partner, binds to CRE (cAMP response element) consensus sequences (5'-TGACGTCA-3') or to AP-1 (activator protein 1) consensus sequences (5'-TGACTCA-3'). In the nucleus, contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. In the cytoplasm, interacts with and perturbs HK1- and VDAC1-containing complexes at the mitochondrial outer membrane, thereby impairing mitochondrial membrane potential, inducing mitochondrial leakage and promoting cell death. The phosphorylated form (mediated by ATM) plays a role in the DNA damage response and is involved in the ionizing radiation (IR)-induced S phase checkpoint control and in the recruitment of the MRN complex into the IR-induced foci (IRIF). Exhibits histone acetyltransferase (HAT) activity which specifically acetylates histones H2B and H4 in vitro (PubMed:10821277). In concert with CUL3 and RBX1, promotes the degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. Can elicit oncogenic or tumor suppressor activities depending on the tissue or cell type.SUBUNIT Binds DNA as a dimer and can form a homodimer in the absence of DNA. Can form a heterodimer with JUN. Heterodimerization is essential for its transcriptional activity. Interacts with SMAD3 and SMAD4. Binds through its N-terminal region to UTF1 which acts as a coactivator of ATF2 transcriptional activity. Interacts with the HK1/VDAC1 complex. Interacts with NBN, MRE11, XPO1, KAT5 and CUL3.TISSUE SPECIFICITY Ubiquitously expressed, with more abundant expression in the brain.DOMAIN The nuclear export signal 1 (N-NES) negatively regulates its nuclear localization and transcriptional activity.PTM Phosphorylation of Thr-69 by MAPK14 and MAPK11, and at Thr-71 by MAPK1/ERK2, MAPK3/ERK1, MAPK11, MAPK12 and MAPK14 in response to external stimulus like insulin causes increased transcriptional activity (PubMed:9430721, PubMed:12110590). Phosphorylated by PLK3 following hyperosmotic stress (PubMed:21098032). Also phosphorylated and activated by JNK and CaMK4 (PubMed:8855261). ATM-mediated phosphorylation at Ser-490 and Ser-498 stimulates its function in DNA damage response (PubMed:15916964). Phosphorylation at Ser-62, Thr-73 and Ser-121 activates its transcriptional activity (PubMed:15105425). Phosphorylation at Thr-69 or Thr-71 enhances acetylation of histones H2B and H4 (PubMed:10821277).SIMILARITY Belongs to the bZIP family. ATF subfamily.CAUTION Appears to have histone acetyltransferase (HAT) activity, specifically towards histones H2B and H4 in vitro (PubMed:10821277). However, it is not clear if this activity is genuine or caused by contamination with other histone acetyltransferases in the assay. UniProt P15336 O-phospho-L-threonine at 71 71 EQUAL O-phospho-L-threonine at 69 69 EQUAL 1 EQUAL 505 EQUAL Reactome DB_ID: 5632949 1 Reactome DB_ID: 8944392 1 p-T69,T71-ATF2:PTEN gene [nucleoplasm] p-T69,T71-ATF2:PTEN gene Reactome DB_ID: 450243 1 O-phospho-L-threonine at 71 71 EQUAL O-phospho-L-threonine at 69 69 EQUAL 1 EQUAL 505 EQUAL Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 8944392 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944392 Reactome R-HSA-8944392 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944392.1 Reactome Database ID Release 82 8944397 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944397 Reactome R-HSA-8944397 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944397.1 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 2.7.11.1 mTORC1 phosphorylates MAF1 mTORC1 phosphorylates MAF1 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). Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-11-03 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 113592 3 Reactome DB_ID: 8944460 1 UniProt:Q9H063 MAF1 MAF1 MAF1 FUNCTION Plays a role in the repression of RNA polymerase III-mediated transcription in response to changing nutritional, environmental and cellular stress conditions to balance the production of highly abundant tRNAs, 5S rRNA, and other small non-coding RNAs with cell growth and maintenance (PubMed:18377933, PubMed:20233713, PubMed:20516213, PubMed:20543138). Also plays a key role in cell fate determination by promoting mesorderm induction and adipocyte differentiation (By similarity). Mechanistically, associates with the RNA polymerase III clamp and thereby impairs its recruitment to the complex made of the promoter DNA, TBP and the initiation factor TFIIIB (PubMed:20887893, PubMed:17505538). When nutrients are available and mTOR kinase is active, MAF1 is hyperphosphorylated and RNA polymerase III is engaged in transcription. Stress-induced MAF1 dephosphorylation results in nuclear localization, increased targeting of gene-bound RNA polymerase III and a decrease in the transcriptional readout (PubMed:26941251). Additionally, may also regulate RNA polymerase I and RNA polymerase II-dependent transcription through its ability to regulate expression of the central initiation factor TBP (PubMed:17499043).SUBUNIT Interacts with TFIIIB subunits BRF1 and BRF2 (PubMed:17505538, PubMed:18377933). Interacts with Pol III subunit POLR3F. Interacts with TFIIIC subunit GTF3C1 (PubMed:18377933).PTM Phosphorylated at Ser-60, Ser-68 and Ser-75; the major sites of phosphorylation. Nuclear accumulation correlates with a concomitant dephosphorylation. Phosphorylation may attenuate its RNA polymerase III-repressive function.PTM Sumoylated with SUMO1 and SUMO2, mainly on Lys-35. Desumoylated by SENP1. SUMOylation promotes the ability of MAF1 to repress transcription and suppress colony formation.SIMILARITY Belongs to the MAF1 family. UniProt Q9H063 1 EQUAL 256 EQUAL Reactome DB_ID: 8944455 1 O-phospho-L-serine at 60 60 EQUAL O-phospho-L-serine at 68 68 EQUAL O-phospho-L-serine at 75 75 EQUAL 1 EQUAL 256 EQUAL Reactome DB_ID: 29370 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5672812 lysosomal membrane GO 0005765 MTORC1:Ragulator:Rag:GNP:RHEB:GTP [lysosomal membrane] MTORC1:Ragulator:Rag:GNP:RHEB:GTP Ragulator:Rag:GNP heterodimers:mTORC1:RHEB:GTP Reactome DB_ID: 165189 1 RHEB:GTP [lysosomal membrane] RHEB:GTP Reactome DB_ID: 29438 1 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI 37565 Reactome DB_ID: 165190 1 UniProt:Q15382 RHEB RHEB RHEB RHEB2 FUNCTION Activates the protein kinase activity of mTORC1, and thereby plays a role in the regulation of apoptosis. Stimulates the phosphorylation of S6K1 and EIF4EBP1 through activation of mTORC1 signaling. Has low intrinsic GTPase activity.ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Inactivated by TSC1-TSC2 via the GTPase activating protein (GAP) domain of TSC2.SUBUNIT Binds to mTORC1 in a guanyl nucleotide-independent manner. Interacts directly with MTOR, MLST8 and RPTOR. Interacts with TSC2. Interacts (when prenylated) with PDE6D; this promotes release from membranes.TISSUE SPECIFICITY Ubiquitous. Highest levels observed in skeletal and cardiac muscle.PTM Farnesylation is important for efficiently activating mTORC1-mediated signaling.PTM Phosphorylation by MAPKAPK5 impairs GTP-binding and inactivation.MISCELLANEOUS The conserved catalytic Gln-64 found in other Ras-like GTPases seems not to be involved in GTP hydrolysis in RHEB.SIMILARITY Belongs to the small GTPase superfamily. Rheb family. UniProt Q15382 1 EQUAL 181 EQUAL Reactome Database ID Release 82 165189 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165189 Reactome R-HSA-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-HSA-165189.1 Reactome DB_ID: 5653972 1 mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 [lysosomal membrane] mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Ragulator:Rag:GNP heterodimers:mTORC1 Reactome DB_ID: 8952725 1 Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 [lysosomal membrane] Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Reactome DB_ID: 5215938 1 UniProt:Q8NBW4 SLC38A9 SLC38A9 URLC11 SLC38A9 FUNCTION Lysosomal amino acid transporter involved in the activation of mTORC1 in response to amino acid levels. Probably acts as an amino acid sensor of the Rag GTPases and Ragulator complexes, 2 complexes involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids (PubMed:25561175, PubMed:25567906, PubMed:29053970). Following activation by amino acids, the Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. SLC38A9 mediates transport of amino acids with low capacity and specificity with a slight preference for polar amino acids (PubMed:25561175, PubMed:25567906). Acts as an arginine sensor (PubMed:25567906, PubMed:29053970). Following activation by arginine binding, mediates transport of leucine, tyrosine and phenylalanine with high efficiency, and is required for the efficient utilization of these amino acids after lysosomal protein degradation (PubMed:29053970).ACTIVITY REGULATION Amino acid transport is sodium-dependent (By similarity). Transport of leucine, tyrosine and phenylalanine is increased by arginine binding (PubMed:29053970).SUBUNIT Associated component of the Ragulator complex (composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5). Associated component of the Rag GTPases heterodimers (composed of RRAGA, RRAGB, RRAGC and RRAGD). Interacts with TM4SF5 (PubMed:30956113).DOMAIN The cytosolic N-terminus part of the protein mediates interaction with the Ragulator complex and the Rag GTPases heterodimers.PTM Glycosylated.SIMILARITY Belongs to the amino acid/polyamine transporter 2 family. SLC38A9 subfamily. UniProt Q8NBW4 1 EQUAL 561 EQUAL Reactome DB_ID: 5653979 1 Ragulator:RagA,B:GTP:RagC,D:GDP [lysosomal membrane] Ragulator:RagA,B:GTP:RagC,D:GDP Reactome DB_ID: 5653921 1 Ragulator [lysosomal membrane] Ragulator Reactome DB_ID: 5653581 1 UniProt:Q9UHA4 LAMTOR3 LAMTOR3 MAP2K1IP1 MAPKSP1 LAMTOR3 PRO2783 FUNCTION As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.SUBUNIT Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:20381137, PubMed:22980980). Interacts with LAMTOR1 and LAMTOR2; the interaction is direct (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid availability (PubMed:20381137). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913). Interacts with MAP2K1/MEK1 and MAPK2 (By similarity). Interacts with MORG1 (By similarity).SIMILARITY Belongs to the LAMTOR3 family. UniProt Q9UHA4 1 EQUAL 124 EQUAL Reactome DB_ID: 5655441 1 UniProt:O43504 LAMTOR5 LAMTOR5 HBXIP XIP LAMTOR5 FUNCTION As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. When complexed to BIRC5, interferes with apoptosome assembly, preventing recruitment of pro-caspase-9 to oligomerized APAF1, thereby selectively suppressing apoptosis initiated via the mitochondrial/cytochrome c pathway. Down-regulates hepatitis B virus (HBV) replication.SUBUNIT Homodimer (PubMed:21059355). Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5. LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid availability (PubMed:22980980). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913). Interacts with phosphorylated BIRC5; the resulting complex binds pro-caspase-9, as well as active caspase-9, but much less efficiently (PubMed:12773388). Interacts with SUPV3L1 (PubMed:16176273).SUBUNIT (Microbial infection) Interacts with hepatitis B virus (HBV) oncoprotein HBX C-terminus.TISSUE SPECIFICITY Highly expressed in skeletal and cardiac muscle, followed by pancreas, kidney, liver, brain, placenta and lung. Elevated levels in both cancerous and non-cancerous liver tissue of patients with chronic HBV infection compared with hepatic tissue without HBV infection.MISCELLANEOUS Suppression of caspase activation by the BIRC5/HBXIP complex is increased in the presence of HBX.SIMILARITY Belongs to the LAMTOR5 family. UniProt O43504 1 EQUAL 91 EQUAL Reactome DB_ID: 5653582 1 UniProt:Q6IAA8 LAMTOR1 LAMTOR1 PDRO PP7157 LAMTOR1 C11orf59 FUNCTION As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. LAMTOR1 is directly responsible for anchoring the Ragulator complex to membranes. Also required for late endosomes/lysosomes biogenesis it may regulate both the recycling of receptors through endosomes and the MAPK signaling pathway through recruitment of some of its components to late endosomes. May be involved in cholesterol homeostasis regulating LDL uptake and cholesterol release from late endosomes/lysosomes. May also play a role in RHOA activation. Involved in the control of embryonic stem cells differentiation; together with FLCN it is necessary to recruit and activate RRAGC/RagC and RRAGD/RagD at the lysosomes, and to induce exit of embryonic stem cells from pluripotency via non-canonical, mTOR-independent TFE3 inactivation (By similarity).SUBUNIT Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:20381137, PubMed:22980980). Interacts with LAMTOR2 and LAMTOR3; the interaction is direct (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid availability (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913). Interacts with RRAGB and RRAGD; the interaction is direct indicating that it probably constitutes the main RAG-interacting subunit of the Ragulator complex (PubMed:22980980). Interacts with MMP14 (PubMed:19654316). Interacts with CDKN1B; prevents the interaction of CDKN1B with RHOA leaving RHOA in a form accessible to activation by ARHGEF2 (PubMed:19654316). Interacts with PIP4P1 (PubMed:29644770).INDUCTION Down-regulated by cholesterol (at protein level).SIMILARITY Belongs to the LAMTOR1 family. UniProt Q6IAA8 2 EQUAL 161 EQUAL Reactome DB_ID: 5655432 1 UniProt:Q0VGL1 LAMTOR4 LAMTOR4 LAMTOR4 C7orf59 FUNCTION As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated.SUBUNIT Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:22980980). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid availability (PubMed:22980980). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913).SIMILARITY Belongs to the LAMTOR4 family. UniProt Q0VGL1 1 EQUAL 99 EQUAL Reactome DB_ID: 5653583 1 UniProt:Q9Y2Q5 LAMTOR2 LAMTOR2 MAPBPIP ROBLD3 LAMTOR2 HSPC003 FUNCTION As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.SUBUNIT Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:20381137, PubMed:22980980). Interacts with LAMTOR1 and LAMTOR3; the interaction is direct (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid availability (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Interacts with MAPK1 and MAP2K1 (By similarity). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913).SIMILARITY Belongs to the GAMAD family. UniProt Q9Y2Q5 1 EQUAL 125 EQUAL Reactome Database ID Release 82 5653921 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653921 Reactome R-HSA-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-HSA-5653921.1 Reactome DB_ID: 5653945 1 RagA,B:GTP:RagC,D:GDP [cytosol] RagA,B:GTP:RagC,D:GDP Converted from EntitySet in Reactome Reactome DB_ID: 5653964 1 RRAGC,RRAGD:GDP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 5653946 1 RRAGA, RRAGB:GTP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 5653945 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653945 Reactome R-HSA-5653945 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653945.2 Reactome Database ID Release 82 5653979 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653979 Reactome R-HSA-5653979 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653979.2 Reactome Database ID Release 82 8952725 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8952725 Reactome R-HSA-8952725 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8952725.3 Reactome DB_ID: 377400 1 mTORC1 [cytosol] mTORC1 MLST8:MTOR:RPTOR mLST8:mTOR:Raptor Reactome DB_ID: 165676 1 1 EQUAL 326 EQUAL Reactome DB_ID: 165662 1 1 EQUAL 2549 EQUAL Reactome DB_ID: 3006727 1 UniProt:Q8N122 RPTOR RPTOR RPTOR RAPTOR KIAA1303 FUNCTION Involved in the control of the mammalian target of rapamycin complex 1 (mTORC1) activity which regulates cell growth and survival, and autophagy in response to nutrient and hormonal signals; functions as a scaffold for recruiting mTORC1 substrates. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Involved in ciliogenesis. mTORC1 complex in excitatory neuronal transmission is required for the prosocial behavior induced by the psychoactive substance lysergic acid diethylamide (LSD) (By similarity).SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR (PubMed:12150925, PubMed:12408816, PubMed:17386266, PubMed:25940091). mTORC1 binds to and is inhibited by FKBP12-rapamycin (PubMed:12408816, PubMed:15066126). Binds directly to 4EBP1 and RPS6KB1 independently of its association with MTOR (PubMed:12150925, PubMed:12150926). Binds preferentially to poorly or non-phosphorylated forms of EIF4EBP1, and this binding is critical to the ability of MTOR to catalyze phosphorylation (PubMed:12747827). Forms a complex with MTOR under both leucine-rich and -poor conditions. Interacts with ULK1 in a nutrient-dependent manner; the interaction is reduced during starvation (PubMed:19211835). Interacts (when phosphorylated by AMPK) with 14-3-3 protein, leading to inhibition of its activity (PubMed:18439900). Interacts with SPAG5; SPAG5 competes with MTOR for RPTOR-binding, resulting in decreased mTORC1 formation. Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). Interacts with G3BP1. The complex formed with G3BP1 AND SPAG5 is increased by oxidative stress (PubMed:23953116). Interacts with HTR6 (PubMed:23027611). Interacts with PIH1D1 (PubMed:24036451). Interacts with LARP1 (PubMed:25940091). Interacts with BRAT1 (PubMed:25657994). Interacts with SIK3 (PubMed:30232230).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein F17; this interaction dysregulates mTOR.TISSUE SPECIFICITY Highly expressed in skeletal muscle, and in a lesser extent in brain, lung, small intestine, kidney and placenta. Isoform 3 is widely expressed, with highest levels in nasal mucosa and pituitary and lowest in spleen.PTM Insulin-stimulated phosphorylation at Ser-863 by MTOR and MAPK8 up-regulates mTORC1 activity. Osmotic stress also induces phosphorylation at Ser-696, Thr-706 and Ser-863 by MAPK8. Ser-863 phosphorylation is required for phosphorylation at Ser-855 and Ser-859. In response to nutrient limitation, phosphorylated by AMPK; phosphorylation promotes interaction with 14-3-3 proteins, leading to negative regulation of the mTORC1 complex. In response to growth factors, phosphorylated at Ser-719, Ser-721 and Ser-722 by RPS6KA1, which stimulates mTORC1 activity.SIMILARITY Belongs to the WD repeat RAPTOR family. UniProt Q8N122 1 EQUAL 1335 EQUAL Reactome Database ID Release 82 377400 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377400 Reactome R-HSA-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-HSA-377400.1 Reactome Database ID Release 82 5653972 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653972 Reactome R-HSA-5653972 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653972.3 Reactome Database ID Release 82 5672812 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5672812 Reactome R-HSA-5672812 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5672812.2 Reactome Database ID Release 82 8944450 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944450 Reactome Database ID Release 82 8944454 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944454 Reactome R-HSA-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-HSA-8944454.1 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 MAF1 translocates to the nucleus MAF1 translocates to the nucleus 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). Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-11-03 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 8944460 1 1 EQUAL 256 EQUAL Reactome DB_ID: 8944422 1 1 EQUAL 256 EQUAL Reactome Database ID Release 82 8944457 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944457 Reactome R-HSA-8944457 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944457.3 INHIBITION Reactome Database ID Release 82 8944458 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944458 Reactome R-HSA-8944458 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944458.1 Reactome DB_ID: 5672812 MAF1 binds the PTEN gene promoter MAF1 binds the PTEN gene promoter The transcription factor MAF1 binds to the promoter region of the PTEN gene to stimulate PTEN transcription (Li et al. 2016). MAF1 is known as a transcriptional repressor of RNA polymerase III-dependent genes, such as genes encoding transport RNAs (tRNAs). Phosphorylation of MAF1 by the mTORC1 complex inhibits MAF1 translocation to the nucleus and transcriptional activity of MAF1 (Shor et al. 2010, Michels et al. 2010). Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-11-03 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 8944422 1 1 EQUAL 256 EQUAL Reactome DB_ID: 5632949 1 Reactome DB_ID: 8944433 1 MAF1:PTEN gene [nucleoplasm] MAF1:PTEN gene Reactome DB_ID: 8944422 1 1 EQUAL 256 EQUAL Reactome DB_ID: 5632949 1 Reactome Database ID Release 82 8944433 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944433 Reactome R-HSA-8944433 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944433.1 Reactome Database ID Release 82 8944420 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944420 Reactome R-HSA-8944420 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944420.1 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 PTEN gene transcription is stimulated by TP53, EGR1, PPARG, ATF2, MAF1, and inhibited by NR2E1, SALL4, MECOM, SNAI1, SNAI2, JUN PTEN gene transcription is stimulated by TP53, EGR1, PPARG, ATF2, MAF1, and inhibited by NR2E1, SALL4, MECOM, SNAI1, SNAI2, JUN PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers. TP53 (p53) stimulates PTEN transcription (Stambolic et al. 2000, Singh et al. 2002). PTEN, acting as a negative regulator of PI3K/AKT signaling, affects cell survival, cell cycling, proliferation and migration. PTEN regulates TP53 stability by inhibiting AKT-mediated activation of TP53 ubiquitin ligase MDM2, and thus enhances TP53 transcriptional activity and its own transcriptional activation by TP53. Beside their cross-regulation, PTEN and TP53 can interact and cooperate to regulate survival or apoptotic phenomena (Stambolic et al. 2000, Singh et al. 2002, Nakanishi et al. 2014).<br>In response to UV induced DNA damage, PTEN transcription is stimulated by binding of the transcription factor EGR1 to the promoter region of PTEN (Virolle et al. 2001).<br>PTEN transcription is also stimulated by binding of the activated nuclear receptor PPARG (PPARgamma) to peroxisome proliferator response elements (PPREs) in the promoter of the PTEN gene (Patel et al. 2001), binding of the ATF2 transcription factor, activated by stress kinases of the p38 MAPK family, to ATF response elements in the PTEN gene promoter (Shen et al. 2006) and by the transcription factor MAF1 (Li et al. 2016).<br>NR2E1 (TLX) associated with transcription repressors binds the evolutionarily conserved TLX consensus site in the PTEN promoter. NR2E1 inhibits PTEN transcription by associating with various transcriptional repressors, probably in a cell type or tissue specific manner. PTEN transcription is inhibited when NR2E1 forms a complex with ATN1 (atrophin-1) (Zhang et al. 2006, Yokoyama et al. 2008), KDM1A (LSD1) histone methyltransferase containing CoREST complex (Yokoyama et al. 2008), or histone deacetylases HDAC3, HDAC5 or HDAC7 (Sun et al. 2007).<br>Binding of the transcriptional repressor SNAI1 (Snail1) to the PTEN promoter represses PTEN transcription. SNAI1-mediated repression of PTEN transcription may require phosphorylation of SNAI1 on serine residue S246. Binding of SNAI1 to the PTEN promoter increases in response to ionizing radiation and is implicated in SNAI1-mediated resistance to gamma-radiation induced apoptosis (Escriva et al. 2008). Binding of another Slug/Snail family member SNAI2 (SLUG) to the PTEN gene promoter also represses PTEN transcription (Uygur et al. 2015).<br>Binding of JUN to the AP-1 element in the PTEN gene promoter (Hettinger et al. 2007) inhibits PTEN transcription. JUN partner FOS is not needed for JUN-mediated downregulation of PTEN (Vasudevan et al. 2007).<br>Binding of the transcription factor SALL4 to the PTEN gene promoter (Yang et al. 2008) and SALL4-medaited recruitment of the transcriptional repressor complex NuRD (Lu et al. 2009, Gao et al. 2013), containing histone deacetylases HDAC1 and HDAC2, inhibits the PTEN gene transcription. SALL4-mediated recruitment of DNA methyltransferases (DNMTs) is also implicated in transcriptional repression of PTEN (Yang et al. 2012).<br>Binding of the transcription factor MECOM (EVI1) to the PTEN gene promoter and MECOM-mediated recruitment of polycomb repressor complexes containing BMI1 (supposedly PRC1.4), and EZH2 (PRC2) leads to repression of PTEN transcription (Song et al. 2009, Yoshimi et al. 2011). Authored: Orlic-Milacic, Marija, 2014-12-23 Authored: Salmena, Leonardo, 2016-08-11 Authored: Carracedo, Arkaitz, 2016-08-11 Reviewed: Hwang, Paul M, 2014-12-30 Reviewed: Kang, Ju-Gyeong, 2014-12-30 Reviewed: Wang, Ping-yuan, 2014-12-30 Reviewed: Inga, Alberto, 2016-02-04 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Leslie, Nicholas, 2016-09-30 Reviewed: Kriplani, Nisha, 2016-09-30 Edited: Orlic-Milacic, Marija, 2014-12-23 Reactome DB_ID: 5632949 1 Reactome DB_ID: 2318746 1 ENSEMBL:ENST00000371953 PTEN PTEN ENSEMBL ENST00000371953 1 EQUAL 9027 EQUAL Reactome Database ID Release 82 8944104 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944104 Reactome R-HSA-8944104 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944104.4 24718924 Pubmed 2014 The tumor suppressor PTEN interacts with p53 in hereditary cancer (Review) Nakanishi, Atsuko Kitagishi, Yasuko Ogura, Yasunori Matsuda, Satoru Int. J. Oncol. 44:1813-9 11959846 Pubmed 2002 p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas Singh, B Reddy, Pabbathi G Goberdhan, Andy Walsh, Christine Dao, Su Ngai, Ivan Chou, Ting Chao O-Charoenrat, Pornchai Levine, Arnold J Rao, Pulivarthi H Stoffel, Archontoula Genes Dev. 16:984-93 INHIBITION Reactome Database ID Release 82 8943805 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943805 Reactome R-HSA-8943805 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8943805.1 Reactome DB_ID: 8943781 ACTIVATION Reactome Database ID Release 82 8944083 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944083 Reactome R-HSA-8944083 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944083.1 Reactome DB_ID: 8944084 ACTIVATION Reactome Database ID Release 82 8944413 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944413 Reactome R-HSA-8944413 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944413.1 Reactome DB_ID: 8944392 ACTIVATION Reactome Database ID Release 82 8944185 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944185 Reactome R-HSA-8944185 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944185.1 Reactome DB_ID: 5632941 INHIBITION Reactome Database ID Release 82 8944035 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944035 Reactome R-HSA-8944035 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944035.1 Reactome DB_ID: 8944024 ACTIVATION Reactome Database ID Release 82 8944194 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944194 Reactome R-HSA-8944194 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944194.1 Reactome DB_ID: 8944097 INHIBITION Reactome Database ID Release 82 6807078 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6807078 Reactome R-HSA-6807078 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6807078.1 Reactome DB_ID: 6807085 ACTIVATION Reactome Database ID Release 82 8944446 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944446 Reactome R-HSA-8944446 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944446.1 Reactome DB_ID: 8944433 INHIBITION Reactome Database ID Release 82 8944303 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944303 Reactome R-HSA-8944303 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944303.1 Reactome DB_ID: 8943821 INHIBITION Reactome Database ID Release 82 8944066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944066 Reactome R-HSA-8944066 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944066.1 Reactome DB_ID: 8944060 Reactome Database ID Release 82 8943724 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943724 Reactome R-HSA-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-HSA-8943724.1 Regulation of PTEN mRNA translation Regulation of PTEN mRNA translation MicroRNAs miR-17, miR-19a, miR-19b, miR-20a, miR-20b, miR-21, miR-22, miR-25, miR 26A1, miR 26A2, miR-93, miR-106a, miR-106b, miR 205, and miR 214 and bind PTEN mRNA and inhibit its translation into protein. These microRNAs are altered in cancer and can account for changes in PTEN levels. There is evidence that PTEN mRNA translation is also inhibited by other microRNAs, such as miR-302 and miR-26B, and these microRNAs will be annotated when additional experimental details become available (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, Zhang et al. 2010, Tay et al. 2011, Qu et al. 2012, 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). Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Salmena, Leonardo, 2016-08-11 Authored: Orlic-Milacic, Marija, 2016-10-28 Reviewed: Leslie, Nicholas, 2016-09-30 Reviewed: Kriplani, Nisha, 2016-09-30 Edited: Orlic-Milacic, Marija, 2017-05-09 miR-17 microRNA binds PTEN mRNA miR-17 microRNA binds PTEN mRNA MicroRNA miR-17-5p, one of the two mature products of miR-17, binds the 3'UTR of PTEN mRNA (Xiao et al. 2008, Poliseno et al. 2010). miR-17 causes reduction in both PTEN mRNA and protein levels and is thus shown to function as a part of the endonucleolytic RISC. It is possible that miR-17 also functions as a part of the nonendonucleolytic RISC. Authored: Orlic-Milacic, Marija, 2016-11-03 Authored: Carracedo, Arkaitz, 2016-08-11 Authored: Salmena, Leonardo, 2016-08-11 Reviewed: Leslie, Nicholas, 2016-09-30 Reviewed: Kriplani, Nisha, 2016-09-30 Edited: Orlic-Milacic, Marija, 2017-05-09 Reactome DB_ID: 2318746 1 1 EQUAL 9027 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 8944485 1 miR-17 RISC [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 8944487 1 miR-17 RISC:PTEN mRNA [cytosol] miR-17 RISC:PTEN mRNA Reactome DB_ID: 2318746 1 1 EQUAL 9027 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 8944485 1 Reactome Database ID Release 82 8944487 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944487 Reactome R-HSA-8944487 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944487.1 Reactome Database ID Release 82 8944483 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944483 Reactome R-HSA-8944483 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944483.4 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 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 INHIBITION Reactome Database ID Release 82 8948591 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948591 Reactome R-HSA-8948591 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948591.1 Reactome DB_ID: 8948581 miR-17 RISC:VAPA mRNA [cytosol] miR-17 RISC:VAPA mRNA Reactome DB_ID: 8945712 1 ENSEMBL:ENST00000340541 VAPA VAPA ENSEMBL ENST00000340541 Converted from EntitySet in Reactome Reactome DB_ID: 8944485 1 Reactome Database ID Release 82 8948581 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948581 Reactome R-HSA-8948581 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948581.1 INHIBITION Reactome Database ID Release 82 8948584 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948584 Reactome R-HSA-8948584 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948584.1 Reactome DB_ID: 8948580 miR-17 RISC:CNOT6L mRNA [cytosol] miR-17 RISC:CNOT6L mRNA Reactome DB_ID: 8945708 1 ENSEMBL:ENST00000264903 CNOT6L CNOT6L ENSEMBL ENST00000264903 Converted from EntitySet in Reactome Reactome DB_ID: 8944485 1 Reactome Database ID Release 82 8948580 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948580 Reactome R-HSA-8948580 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948580.1 miR-19a microRNA binds PTEN mRNA miR-19a microRNA binds PTEN mRNA MicroRNA miR-19a-3p, one of the two mature products of miR-19a, binds the 3'UTR of PTEN mRNA (Xiao et al. 2008, Poliseno, Salmena, Riccardi et al. 2010). miR-19a microRNA causes reduction in both PTEN mRNA and protein levels and is thus shown to function as a part of the endonucleolytic RISC. It is possible that miR-19a microRNA also functions as a part of the nonendonucleolytic RISC. Authored: Orlic-Milacic, Marija, 2016-11-03 Reviewed: Leslie, Nicholas, 2016-09-30 Reviewed: Kriplani, Nisha, 2016-09-30 Edited: Orlic-Milacic, Marija, 2017-05-09 Converted from EntitySet in Reactome Reactome DB_ID: 8948559 1 miR-19a RISC [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 2318746 1 1 EQUAL 9027 EQUAL Reactome DB_ID: 8944524 1 miR-19a RISC:PTEN mRNA [cytosol] miR-19a RISC:PTEN mRNA Converted from EntitySet in Reactome Reactome DB_ID: 8948559 1 Reactome DB_ID: 2318746 1 1 EQUAL 9027 EQUAL Reactome Database ID Release 82 8944524 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944524 Reactome R-HSA-8944524 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944524.1 Reactome Database ID Release 82 8944522 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8944522 Reactome R-HSA-8944522 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8944522.4 INHIBITION Reactome Database ID Release 82 8948604 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948604 Reactome R-HSA-8948604 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948604.1 Reactome DB_ID: 8948605 miR-19a RISC:CNOT6L mRNA [cytosol] miR-19a RISC:CNOT6L mRNA Converted from EntitySet in Reactome Reactome DB_ID: 8948559 1 Reactome DB_ID: 8945708 1 Reactome Database ID Release 82 8948605 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948605 Reactome R-HSA-8948605 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948605.1 INHIBITION Reactome Database ID Release 82 8948600 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948600 Reactome R-HSA-8948600 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948600.1 Reactome DB_ID: 8948593 miR-19a RISC:VAPA mRNA [cytosol] miR-19a RISC:VAPA mRNA Converted from EntitySet in Reactome Reactome DB_ID: 8948559 1 Reactome DB_ID: 8945712 1 Reactome Database ID Release 82 8948593 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948593 Reactome R-HSA-8948593 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948593.1 miR-19b microRNA binds PTEN mRNA miR-19b microRNA binds PTEN mRNA MicroRNA miR-19b, encoded by two genomic loci, MIR19B1 and MIR19B2, is homologous to miR-19a and also binds to the 3'UTR of PTEN mRNA (Polseno, Salmena, Zhang et al. 2010). miR-19b microRNA causes reduction in both PTEN mRNA and protein levels and is thus shown to function as a part of the endonucleolytic RISC. It is possible that miR-19b microRNA also functions as a part of the nonendonucleolytic RISC. Authored: Orlic-Milacic, Marija, 2016-11-03 Reviewed: Leslie, Nicholas, 2016-09-30 Reviewed: Kriplani, Nisha, 2016-09-30 Edited: Orlic-Milacic, Marija, 2017-05-09 Converted from EntitySet in Reactome Reactome DB_ID: 8948558 1 miR-19b RISC [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 2318746 1 1 EQUAL 9027 EQUAL Reactome DB_ID: 8948568 1 miR-19b RISC:PTEN mRNA [cytosol] miR-19b RISC:PTEN mRNA Converted from EntitySet in Reactome Reactome DB_ID: 8948558 1 Reactome DB_ID: 2318746 1 1 EQUAL 9027 EQUAL Reactome Database ID Release 82 8948568 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948568 Reactome R-HSA-8948568 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948568.1 Reactome Database ID Release 82 8948569 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948569 Reactome R-HSA-8948569 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948569.4 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 INHIBITION Reactome Database ID Release 82 8948611 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948611 Reactome R-HSA-8948611 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948611.1 Reactome DB_ID: 8948610 miR-19b RISC:CNOT6L mRNA [cytosol] miR-19b RISC:CNOT6L mRNA Reactome DB_ID: 8945708 1 Converted from EntitySet in Reactome Reactome DB_ID: 8948558 1 Reactome Database ID Release 82 8948610 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948610 Reactome R-HSA-8948610 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948610.1 INHIBITION Reactome Database ID Release 82 8948532 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948532 Reactome R-HSA-8948532 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8948532.1 Reactome DB_ID: 8948521 miR-19b RISC:PTENP1 mRNA [cytosol] miR-19b RISC:PTENP1 mRNA Reactome DB_ID: 8945698 1 ENSEMBL:ENST00000532280 PTENP1 PTENP1 ENSEMBL ENST00000532280 Converted from EntitySet in Reactome Reactome DB_ID: 8948558 1 Reactome Database ID Release 82 8948521 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8948521 Reactome R-HSA-8948521 1 Reactome stable identifier. Use this URL to co