BioPAX pathway converted from "PIP3 activates AKT signaling" in the Reactome database. PIP3 activates AKT signaling PIP3 activates AKT signaling PI3K/AKT Signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> RAC1,RAC2,RHOG activate PI3K RAC1,RAC2,RHOG activate PI3K This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9823925 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: 9823932 1 cytosol GO 0005829 PI3K alpha [cytosol] PI3K alpha Converted from EntitySet in Reactome Reactome DB_ID: 9823930 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] Mus musculus NCBI Taxonomy 10090 UniProt P26450 Reactome DB_ID: 9027214 1 UniProt:P42337 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. Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). 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. Also has serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS. Plays a role in the positive regulation of phagocytosis and pinocytosis (PubMed:19604150).PATHWAY Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.SUBUNIT Heterodimer of a catalytic subunit PIK3CA and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3) (PubMed:8139567). Interacts with IRS1 in nuclear extracts (PubMed:15197263). Interacts with RUFY3. Interacts with RASD2. Interacts with APPL1 (By similarity). Interacts with HRAS and KRAS (PubMed:17540175). Interaction with HRAS/KRAS is required for PI3K pathway signaling and cell proliferation stimulated by EGF and FGF2 (PubMed:17540175). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (By similarity).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.DISRUPTION PHENOTYPE Lethal. Embryonic fibroblasts cells are resistant to oncogenic transformation induced by oncogenic receptor tyrosine kinases (RTKs), are unable to differentiate into adipocytes and deficient in cellular signaling in response to various growth factors. Defective responsiveness to insulin led to reduced somatic growth, hyperinsulinemia, glucose intolerance, hyperphagia and increased adiposity.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt P42337 Chain Coordinates 1 EQUAL 1068 EQUAL Reactome Database ID Release 82 9823932 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823932 Reactome R-MMU-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-MMU-198379.1 Reactome DB_ID: 9823934 1 RAC1:GTP,RAC2:GTP,RHOG:GTP:PI3K alpha [plasma membrane] RAC1:GTP,RAC2:GTP,RHOG:GTP:PI3K alpha Reactome DB_ID: 9823932 1 Converted from EntitySet in Reactome Reactome DB_ID: 9823925 1 Reactome Database ID Release 82 9823934 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823934 Reactome R-MMU-114540 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114540.1 Reactome Database ID Release 82 9823936 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823936 Reactome R-MMU-114542 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114542.1 PIP3 produced by PI3K activity is essential for receptor-driven stimulation of Rac activation, but PI3K also lies downstream of Rac, as Rac1 can form a complex with PI3K alpha leading to its activation. 8645157 Pubmed 1996 Rac GTPase interacts specifically with phosphatidylinositol 3-kinase Bokoch, GM Vlahos, CJ Wang, Y Knaus, UG Traynor-Kaplan, AE Biochem J 315:775-9 7744773 Pubmed 1995 Phosphoinositide 3-kinase inhibition spares actin assembly in activating platelets but reverses platelet aggregation Kovacsovics, TJ Bachelot, C Toker, A Vlahos, CJ Duckworth, B Cantley, Lewis C Hartwig, JH J Biol Chem 270:11358-66 11803464 Pubmed 2002 Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-kappaB Murga, C Zohar, M Teramoto, H Gutkind, JS Oncogene 21:207-16 7627555 Pubmed 1995 PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase Hawkins, PT Eguinoa, A Qiu, RG Stokoe, D Cooke, FT Walters, R Wennström, S Claesson-Welsh, Lena Evans, T Symons, M Curr Biol 5:393-403 inferred by electronic annotation IEA GO IEA 2.7.1.153 PI3K phosphorylates PIP2 to PIP3 PI3K phosphorylates PIP2 to PIP3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 179856 1 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) [ChEBI:58456] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) 2,3-bis(alkanoyloxy)propyl (1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-bis(phosphonatooxy)cyclohexyl phosphate a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) ChEBI 58456 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 179838 1 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) [ChEBI:57836] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) 2,3-bis(alkanoyloxy)propyl (1S,2S,3R,4S,5S,6S)-2,6-dihydroxy-3,4,5-tris(phosphonatooxy)cyclohexyl phosphate ChEBI 57836 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9876873 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 9876874 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9876874 Reactome Database ID Release 82 9876880 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9876880 Reactome R-MMU-2316434 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2316434.1 GO 0051897 GO biological process A number of different extracellular signals converge on PI3K activation. PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as FGFR (Ong et al. 2001, Eswarakumar et al. 2005), KIT (Chian et al. 2001, Ronnstrand 2004, Reber et al. 2006), PDGF (Coughlin et al. 1989, Fantl et al. 1992, Heldin et al. 1998), insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995), and EGFR and its family members (Rodrigues et al. 2000, Jackson et al. 2004, Kainulainen et al. 2000, Junttila et al. 2009). Other proteins, such as CD28 (Pages et al. 1996, Koyasu 2003, Kane and Weiss, 2003) and TRAT1 (Bruyns et al. 1998, Koyasu 2003, Kolsch et al. 2006), can also trigger PI3K activity.<br><br>In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011). 16612002 Pubmed 2006 Normal T-cell development and immune functions in TRIM-deficient mice Kolsch, U Arndt, B Reinhold, D Lindquist, JA Juling, N Kliche, S Pfeffer, K Bruyns, E Schraven, B Simeoni, L Mol Cell Biol 26:3639-48 10722704 Pubmed 2000 A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis Kainulainen, V Sundvall, M Määttä, JA Santiestevan, E Klagsbrun, Michael Elenius, K J Biol Chem 275:8641-9 21827948 Pubmed 2011 Dynamics of the phosphoinositide 3-kinase p110? interaction with p85? and membranes reveals aspects of regulation distinct from p110? Burke, John E Vadas, Oscar Berndt, Alex Finegan, Tara Perisic, O Williams, RL Structure 19:1127-37 11353842 Pubmed 2001 Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins Ong, SH Hadari, YR Gotoh, N Guy, GR Schlessinger, J Lax, I Proc Natl Acad Sci U S A 98:6074-9 2466336 Pubmed 1989 Role of phosphatidylinositol kinase in PDGF receptor signal transduction Coughlin, SR Escobedo, JA Williams, LT Science 243:1191-4 16483568 Pubmed 2006 Stem cell factor and its receptor c-Kit as targets for inflammatory diseases Reber, L Da Silva, CA Frossard, N Eur J Pharmacol 533:327-40 10648629 Pubmed 2000 A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling Rodrigues, GA Falasca, M Zhang, Z Ong, SH Schlessinger, J Mol Cell Biol 20:1448-59 15526160 Pubmed 2004 Signal transduction via the stem cell factor receptor/c-Kit Rönnstrand, Lars Cell Mol Life Sci 61:2535-48 15059917 Pubmed 2004 Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects Jackson, JG St Clair, P Sliwkowski, MX Brattain, Michael G Cancer Res 64:2601-9 12660731 Pubmed 2003 The role of PI3K in immune cells Koyasu, S Nat Immunol 4:313-9 15863030 Pubmed 2005 Cellular signaling by fibroblast growth factor receptors Eswarakumar, VP Lax, I Schlessinger, J Cytokine Growth Factor Rev 16:139-49 8621607 Pubmed 1996 Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association Pagès, F Ragueneau, M Klasen, S Battifora, M Couez, D Sweet, R Truneh, A Ward, SG Olive, D J Biol Chem 271:9403-9 19411071 Pubmed 2009 Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941 Junttila, TT Akita, Robert W Parsons, K Fields, C Lewis Phillips, GD Friedman, LS Sampath, D Sliwkowski, MX Cancer Cell 15:429-40 1381348 Pubmed 1992 Insulin and insulinomimetic agents induce activation of phosphatidylinositol 3'-kinase upon its association with pp185 (IRS-1) in intact rat livers Hadari, Yaron Tzahar, E Nadiv, Orna Rothenberg, Paul Roberts, Charles LeRoith, Derek Yarden, Y Zick, Yehiel J. Biol. Chem. 267:17483-6 11520784 Pubmed 2001 Phosphatidylinositol 3 kinase contributes to the transformation of hematopoietic cells by the D816V c-Kit mutant Chian, R Young, S Danilkovitch-Miagkova, A Rönnstrand, Lars Leonard, E Ferrao, P Ashman, L Linnekin, D Blood 98:1365-73 9687533 Pubmed 1998 T cell receptor (TCR) interacting molecule (TRIM), a novel disulfide-linked dimer associated with the TCR-CD3-zeta complex, recruits intracellular signaling proteins to the plasma membrane Bruyns, E Marie-Cardine, A Kirchgessner, H Sagolla, K Shevchenko, A Mann, M Autschbach, F Bensussan, A Meuer, S Schraven, B J Exp Med 188:561-75 9739761 Pubmed 1998 Signal transduction via platelet-derived growth factor receptors Heldin, Carl-Henrik Ostman, A Rönnstrand, Lars Biochim Biophys Acta 1378:F79-113 19805105 Pubmed 2009 A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane Mandelker, Diana Gabelli, Sandra B Schmidt-Kittler, Oleg Zhu, Jiuxiang Cheong, Ian Huang, Chuan-Hsiang Kinzler, KW Vogelstein, B Amzel, L Mario Proc. Natl. Acad. Sci. U.S.A. 106:16996-7001 7543144 Pubmed 1995 Insulin-like growth factor induces phosphorylation of immunoreactive insulin receptor substrate and its association with phosphatidylinositol-3 kinase in human thymocytes Kooijman, Ron Lauf, Jeroen Kappers, Astrid Rijkers, Ger J. Exp. Med. 182:593-7 1374684 Pubmed 1992 Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways Fantl, WJ Escobedo, JA Martin, GA Turck, CW del Rosario, M McCormick, F Williams, LT Cell 69:413-23 12670391 Pubmed 2003 The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3 Kane, LP Weiss, A Immunol Rev 192:7-20 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 82 9876881 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9876881 Reactome DB_ID: 9876878 IL33:IL1RL1:IL1RAP-1:MYD88 dimer:IRAK1,IRAK4,TRAF6 [plasma membrane] IL33:IL1RL1:IL1RAP-1:MYD88 dimer:IRAK1,IRAK4,TRAF6 Reactome DB_ID: 9849162 1 UniProt:Q62406 Irak1 Irak1 Il1rak 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 (By similarity).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 (By similarity). The TRAF6-PELI1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation (By similarity). Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex (By similarity). Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation (By similarity). Interacts with IL1RL1 (By similarity). Interacts (when polyubiquitinated) with IKBKG/NEMO (By similarity). Interacts with RSAD2/viperin (PubMed:21435586). Interacts with IRAK1BP1 (PubMed:11096118). Interacts with PELI2 (PubMed:12370331). Interacts with ZC3H12A; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (PubMed:22037600). Interacts with IRAK4 (By similarity). Interacts with PELI3 (By similarity). Interacts with PELI1 and TRAF6 (By similarity). Interacts with INAVA; the interaction takes place upon PRR stimulation (By similarity). Interacts (via C-terminus) with NFATC4 (via N-terminus) (By similarity).TISSUE SPECIFICITY Highly expressed in liver, followed by kidney and skeletal muscle.DEVELOPMENTAL STAGE Expressed from 11 dpc to 18 dpc.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 (By similarity).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 (By similarity).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 (By similarity).DISRUPTION PHENOTYPE Mice show a loss in TLR7- and TLR9-mediated IFN-alpha production in plasmacytoid dendritic cells demonstrating an important role in innate immune response.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. UniProt Q62406 1 EQUAL 712 EQUAL Reactome DB_ID: 9876876 1 IL33:IL1RL1:IL1RAP-1:MYD88 dimer [plasma membrane] IL33:IL1RL1:IL1RAP-1:MYD88 dimer Reactome DB_ID: 9849305 1 IL33:IL1RL1:IL1RAP-1 [plasma membrane] IL33:IL1RL1:IL1RAP-1 Reactome DB_ID: 9848865 1 UniProt:Q61730 Il1rap UniProt Q61730 21 EQUAL 570 EQUAL Reactome DB_ID: 9849303 1 IL1RL1:IL33 [plasma membrane] IL1RL1:IL33 Reactome DB_ID: 9849297 1 UniProt:P14719 Il1rl1 UniProt P14719 19 EQUAL 556 EQUAL Reactome DB_ID: 9849301 1 extracellular region GO 0005576 UniProt:Q8BVZ5 Il33 UniProt Q8BVZ5 1 EQUAL 270 EQUAL Reactome Database ID Release 82 9849303 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9849303 Reactome R-MMU-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-MMU-448601.1 Reactome Database ID Release 82 9849305 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9849305 Reactome R-MMU-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-MMU-448571.1 Reactome DB_ID: 9832610 1 MYD88 dimer [cytosol] MYD88 dimer Reactome DB_ID: 9832608 2 UniProt:P22366 Myd88 UniProt P22366 1 EQUAL 296 EQUAL Reactome Database ID Release 82 9832610 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9832610 Reactome R-MMU-193932 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-193932.1 Reactome Database ID Release 82 9876876 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9876876 Reactome R-MMU-8981947 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8981947.1 Reactome DB_ID: 9828388 1 UniProt:P70196 Traf6 Traf6 Traf6 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:15322147, PubMed:17633018). Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation (By similarity). Leads to the activation of NF-kappa-B and JUN. Seems to also play a role in dendritic cells (DCs) maturation and/or activation (PubMed:14499111). Represses c-Myb-mediated transactivation, in B-lymphocytes (By similarity). Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor (PubMed:10421844, PubMed:10215628). Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation (PubMed:10421844, PubMed:17092936). 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 (PubMed:12881420).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer (By similarity). Homooligomer (By similarity). 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 (By similarity). Associates with NGFR, TNFRSF17, IRAK2, IRAK3, PELI2, PELI3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Binds UBE2V1. Interacts with MAVS/IPS1. Interacts with TAX1BP1 (By similarity). Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ. Interacts with IL1RL1. Interacts with AJUBA (By similarity). Interacts with TRAFD1. Interacts with TICAM2. Interacts with ZFAND5. Interacts with ARRB1 and ARRB2 (By similarity). 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) (By similarity). Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with RBCK1 (By similarity). Interacts with LIMD1 (via LIM domains). Interacts with RSAD2/viperin. Interacts with IFIT3 (via N-terminus) (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain). Interacts with CARD14 (By similarity). Interacts with CD40 and MAP3K8; the interaction is required for ERK activation. Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (By similarity). Interacts with TANK; this interaction increases in response to DNA damage (By similarity). Interacts with USP10; this interaction increases in response to DNA damage (By similarity). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (By similarity). Interacts with WDFY3 (PubMed:27330028). Interacts with TRIM13 (By similarity). Interacts with GPS2 (PubMed:22424771). Interacts (via C-terminus) with SASH1 (By similarity). Interacts with LRRC19 (By similarity). Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70 (By similarity). Interacts with AMBRA1; interaction is required to mediate 'Lys-63'-linked ubiquitination of ULK1 (By similarity).TISSUE SPECIFICITY Highly expressed in brain, lung, liver, skeletal muscle, and kidney; lower expression in heart, spleen, and testis.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-461 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (By similarity). Polyubiquitinated; 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-kappa-B signaling upon DNA damage. LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).DISRUPTION PHENOTYPE Abrogation of IL-1-induced activation of NF-kappa-B, MAPK8/JNK and MAPK14/p38. Animals appear normal at birth but become smaller after one week. Show runting, failure of tooth eruption and die after three weeks. Exhibit severe osteopetrosis, thymic atrophy, lymph node deficiency, splenomegaly, and have alopecia and lack sweat glands.SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. UniProt P70196 1 EQUAL 522 EQUAL Reactome DB_ID: 9849130 1 UniProt:Q8R4K2 UniProt Q8R4K2 1 EQUAL 460 EQUAL Reactome Database ID Release 82 9876878 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9876878 Reactome R-MMU-8981951 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8981951.1 PIP3 recruits AKT to the membrane PIP3 recruits AKT to the membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9844166 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 P31750 Reactome DB_ID: 179838 1 Reactome DB_ID: 9833451 1 AKT:PIP3 [plasma membrane] AKT:PIP3 Reactome DB_ID: 179838 1 Converted from EntitySet in Reactome Reactome DB_ID: 9833449 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 9833451 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833451 Reactome R-MMU-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-MMU-2317329.1 Reactome Database ID Release 82 9876887 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9876887 Reactome R-MMU-2317332 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2317332.1 GO 0032148 GO biological process PIP3 generated by PI3K recruits AKT (also known as protein kinase B) to the membrane, through its PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation (Scheid et al. 2002). In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied. 17914025 Pubmed 2008 The role of Akt in the signaling pathway of the glycoprotein Ib-IX induced platelet activation Yin, H Stojanovic, A Hay, N Du, X Blood 111:658-65 12167717 Pubmed 2002 Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B Scheid, MP Marignani, PA Woodgett, JR Mol Cell Biol 22:6247-60 2008 The role of Akt3 in Platelet Activation O'Brien, K Stojanovic, A Hay, N Du, X Arteriosclerosis, Thrombosis, and Vascular Biology 28:e162 inferred by electronic annotation IEA GO IEA PIP3 recruits PDPK1 to the membrane PIP3 recruits PDPK1 to the membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9835485 1 UniProt:Q9Z2A0 UniProt Q9Z2A0 1 EQUAL 556 EQUAL Reactome DB_ID: 179838 1 Reactome DB_ID: 9822541 1 PDPK1:PIP3 [plasma membrane] PDPK1:PIP3 Reactome DB_ID: 9822539 1 1 EQUAL 556 EQUAL Reactome DB_ID: 179838 1 Reactome Database ID Release 82 9822541 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9822541 Reactome R-MMU-109697 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-109697.1 Reactome Database ID Release 82 9876785 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9876785 Reactome R-MMU-2316429 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2316429.1 PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999). 9895304 Pubmed 1999 Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1 Currie, RA Walker, KS Gray, A Deak, M Casamayor, A Downes, CP Cohen, P Alessi, DR Lucocq, J Biochem J 337:575-83 inferred by electronic annotation IEA GO IEA 2.7.11.1 TORC2 (mTOR) phosphorylates AKT at S473 TORC2 (mTOR) phosphorylates AKT at S473 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 9833451 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9833461 1 p-S-AKT:PIP3 [plasma membrane] p-S-AKT:PIP3 Converted from EntitySet in Reactome Reactome DB_ID: 9833459 1 p-S-AKT [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-S473-AKT1 [plasma membrane] Reactome DB_ID: 179838 1 Reactome Database ID Release 82 9833461 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833461 Reactome R-MMU-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-MMU-2317310.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9833475 TORC2 complex [cytosol] TORC2 complex Reactome DB_ID: 9833473 1 UniProt:Q812A5 Prr5 UniProt Q812A5 1 EQUAL 388 EQUAL Reactome DB_ID: 9827078 1 UniProt:Q9JLN9 Mtor UniProt Q9JLN9 1 EQUAL 2549 EQUAL Reactome DB_ID: 9833469 1 UniProt:Q8BKH7 Mapkap1 UniProt Q8BKH7 2 EQUAL 522 EQUAL Reactome DB_ID: 9833465 1 UniProt:Q6QI06 Rictor UniProt Q6QI06 1 EQUAL 1708 EQUAL Reactome DB_ID: 9827074 1 UniProt:Q9DCJ1 Mlst8 UniProt Q9DCJ1 1 EQUAL 326 EQUAL Reactome Database ID Release 82 9833475 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833475 Reactome R-MMU-198626 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198626.1 GO 0004674 GO molecular function Reactome Database ID Release 82 9833476 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833476 Reactome Database ID Release 82 9833486 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833486 Reactome R-MMU-198640 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198640.1 Under conditions of growth and mitogen stimulation S473 phosphorylation of AKT is carried out by mTOR (mammalian Target of Rapamycin). This kinase is found in two structurally and functionally distinct protein complexes, named TOR complex 1 (TORC1) and TOR complex 2 (TORC2). It is TORC2 complex, which is composed of mTOR, RICTOR, SIN1 (also named MAPKAP1) and LST8, that phosphorylates AKT at S473 (Sarbassov et al., 2005). This complex also regulates actin cytoskeletal reorganization (Jacinto et al., 2004; Sarbassov et al., 2004). TORC1, on the other hand, is a major regulator of ribosomal biogenesis and protein synthesis (Hay and Sonenberg, 2004). TORC1 regulates these processes largely by the phosphorylation/inactivation of the repressors of mRNA translation 4E binding proteins (4E BPs) and by the phosphorylation/activation of ribosomal S6 kinase (S6K1). TORC1 is also the principal regulator of autophagy. In other physiological conditions, other kinases may be responsible for AKT S473 phosphorylation.<br> Phosphorylation of AKT on S473 by TORC2 complex is a prerequisite for AKT phosphorylation on T308 by PDPK1 (Scheid et al. 2002, Sarabassov et al. 2005). 19303758 Pubmed 2009 PIKKing on PKB: regulation of PKB activity by phosphorylation Bozulic, L Hemmings, BA Curr Opin Cell Biol 21:256-61 15268862 Pubmed 2004 Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton Sarbassov, DD Ali, SM Kim, DH Guertin, DA Latek, RR Erdjument-Bromage, H Tempst, P Sabatini, DM Curr Biol 14:1296-302 15467718 Pubmed 2004 Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive Jacinto, E Loewith, R Schmidt, A Lin, S Ruegg, MA Hall, A Hall, MN Nat Cell Biol 6:1122-8 15314020 Pubmed 2004 Upstream and downstream of mTOR Hay, N Sonenberg, Nahum Genes Dev 18:1926-45 15718470 Pubmed 2005 Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex Sarbassov, DD Guertin, DA Ali, SM Sabatini, DM Science 307:1098-101 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 9833487 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833487 Reactome DB_ID: 9833484 AKT:PIP3:THEM4/TRIB3 [plasma membrane] AKT:PIP3:THEM4/TRIB3 Reactome DB_ID: 9833451 1 Converted from EntitySet in Reactome Reactome DB_ID: 9833482 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 Q8K4K2 UniProt Q3UUI3 Reactome Database ID Release 82 9833484 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833484 Reactome R-MMU-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-MMU-199453.1 AKT binds PDPK1 AKT binds PDPK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9833461 1 Reactome DB_ID: 9822541 1 Reactome DB_ID: 9876883 1 p-S-AKT:PDPK1:PIP3 [plasma membrane] p-S-AKT:PDPK1:PIP3 Reactome DB_ID: 9833461 1 Reactome DB_ID: 9822541 1 Reactome Database ID Release 82 9876883 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9876883 Reactome R-MMU-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-MMU-2317313.1 Reactome Database ID Release 82 9876885 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9876885 Reactome R-MMU-2317314 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2317314.1 Once phosphorylated on serine residue S473, AKT bound to PIP3 forms a complex with PIP3-bound PDPK1 i.e. PDK1 (Scheid et al. 2002, Sarabassov et al. 2005) inferred by electronic annotation IEA GO IEA AKT phosphorylates targets in the cytosol AKT phosphorylates targets in the cytosol This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.11.1 AKT phosphorylates caspase-9 AKT phosphorylates caspase-9 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 9823799 1 UniProt:Q8C3Q9 Casp9 Casp9 Mch6 Casp9 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) (By similarity).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 increased in the response of cells to genotoxic stress and ABL1/c-Abl activation (By similarity). Interacts with BCL2L10 (By similarity).PTM Cleavages at Asp-353 by granzyme B and at Asp-368 by caspase-3 generate the two active subunits. Caspase-8 and -10 can also be involved in these processing events (By similarity).PTM Phosphorylated at Thr-163 by MAPK1/ERK2. Phosphorylation at Thr-163 is sufficient to block caspase-9 processing and subsequent caspase-3 activation (By similarity). Phosphorylation on Tyr-191 by ABL1/c-Abl; occurs in the response of cells to DNA damage.SIMILARITY Belongs to the peptidase C14A family. UniProt Q8C3Q9 1 EQUAL 416 EQUAL Reactome DB_ID: 29370 1 Reactome DB_ID: 9833439 1 O-phospho-L-serine at 196 (in Homo sapiens) 196 EQUAL O-phospho-L-serine [MOD:00046] 1 EQUAL 416 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9833410 p-T,p-S-AKT [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-T308,S473-AKT1 [cytosol] Reactome Database ID Release 82 9833411 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833411 Reactome Database ID Release 82 9833441 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833441 Reactome R-MMU-198621 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198621.1 GO 0043491 GO biological process AKT can phosphorylate the apoptotic protease caspase-9, inhibiting it. 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 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT phosphorylates MDM2 AKT phosphorylates MDM2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 9833395 1 UniProt:P23804 Mdm2 Mdm2 Mdm2 FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome (PubMed:15195100, PubMed:21804542). Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain (By similarity). Also acts as a ubiquitin ligase E3 toward itself, ARRB1 and ARBB2 (PubMed:11588219). Permits the nuclear export of p53/TP53 (By similarity). Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein (By similarity). Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation (By similarity). Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53 (By similarity). Also a component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways (By similarity). Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus (By similarity). Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation (By similarity). Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells (PubMed:25088421). Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis (PubMed:14642282). 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. Interacts with MTA1 (By similarity). Interacts with AARB2 (PubMed:11588219). Interacts with MTBP (PubMed:10906133). Interacts with PML (PubMed:15195100). Interacts with TBRG1 (PubMed:17110379). 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:21804542). Interacts with ADGRB1; the interaction results in inhibition of MDM2-mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4 stability and regulating synaptic plasticity (PubMed:25751059). Interacts with RPL23A; this interaction may promote p53/TP53 polyubiquitination (By similarity). Interacts with NDUFS1 (PubMed:30879903).TISSUE SPECIFICITY Ubiquitously expressed at low-level throughout embryo development and in adult tissues. MDM2-p90 is much more abundant than MDM2-p76 in testis, brain, heart, and kidney, but in the thymus, spleen, and intestine, the levels of the MDM2 proteins are roughly equivalent.INDUCTION By UV light (PubMed:10075719). Down-regulated by NPAS4 (PubMed:25088421).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-163 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 (By similarity).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 (By similarity).DISRUPTION PHENOTYPE Loss of Dlg4 ubiquitination.SIMILARITY Belongs to the MDM2/MDM4 family. UniProt P23804 1 EQUAL 491 EQUAL Reactome DB_ID: 9833399 1 O-phospho-L-serine at 166 (in Homo sapiens) 166 EQUAL O-phospho-L-serine at 188 (in Homo sapiens) 188 EQUAL 1 EQUAL 491 EQUAL Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9833410 Reactome Database ID Release 82 9833413 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833413 Reactome R-MMU-198599 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198599.1 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). 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 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 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 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 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT phosphorylates IKKalpha AKT phosphorylates IKKalpha This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 9833419 1 UniProt:Q60680 UniProt Q60680 1 EQUAL 745 EQUAL Reactome DB_ID: 29370 1 Reactome DB_ID: 9833422 1 O-phospho-L-threonine at 23 (in Homo sapiens) 23 EQUAL O-phospho-L-threonine [MOD:00047] 1 EQUAL 745 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9833410 Reactome Database ID Release 82 9833424 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833424 Reactome R-MMU-198611 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198611.1 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. 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 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT phosphorylates p21Cip1 and p27Kip1 AKT phosphorylates p21Cip1 and p27Kip1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Converted from EntitySet in Reactome Reactome DB_ID: 9833426 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 P46414 UniProt P39689 Reactome DB_ID: 29370 1 Converted from EntitySet in Reactome Reactome DB_ID: 9833434 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 phospho-Cdkn1b [cytosol] phospho-Cdkn1a [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9833410 Reactome Database ID Release 82 9833436 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833436 Reactome R-MMU-198613 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198613.1 Phosphorylation of p27Kip1 at T157 and of p21Cip1 at T145 by AKT leads to their retention in the cytoplasm, segregating these cyclin-dependent kinase (CDK) inhibitors from cyclin-CDK complexes. 12244303 Pubmed 2002 Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer Viglietto, G Motti, ML Bruni, P Melillo, RM D'Alessio, A Califano, D Vinci, F Chiappetta, G Tsichlis, P Bellacosa, A Fusco, A Santoro, M Nat Med 8:1136-44 11231573 Pubmed 2001 Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells Zhou, B P Liao, Y Xia, W Spohn, B Lee, M H Hung, M C Nat. Cell Biol. 3:245-52 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT phosphorylates TSC2, inhibiting it AKT phosphorylates TSC2, inhibiting it This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 9827038 1 UniProt:Q61037 Tsc2 UniProt Q61037 1 EQUAL 1807 EQUAL Reactome DB_ID: 29370 2 Reactome DB_ID: 9833415 1 O-phospho-L-serine at 939 (in Homo sapiens) 939 EQUAL O-phospho-L-threonine at 1462 (in Homo sapiens) 1462 EQUAL 1 EQUAL 1807 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9833410 Reactome Database ID Release 82 9833417 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9833417 Reactome R-MMU-198609 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198609.1 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. 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 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT phosphorylates AKT1S1 (PRAS40) AKT phosphorylates AKT1S1 (PRAS40) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 9827168 1 UniProt:Q9D1F4 Akt1s1 UniProt Q9D1F4 1 EQUAL 256 EQUAL Reactome DB_ID: 29370 2 Reactome DB_ID: 9834592 1 O-phospho-L-serine at 183 (in Homo sapiens) 183 EQUAL O-phospho-L-threonine at 246 (in Homo sapiens) 246 EQUAL 1 EQUAL 256 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9833410 Reactome Database ID Release 82 9834594 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834594 Reactome R-MMU-200143 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-200143.1 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). 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 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT phosphorylates MKRN1 AKT phosphorylates MKRN1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 9858125 1 UniProt:Q9QXP6 Mkrn1 UniProt Q9QXP6 1 EQUAL 482 EQUAL Reactome DB_ID: 9915305 1 O-phospho-L-serine at 109 (in Homo sapiens) 109 EQUAL 1 EQUAL 482 EQUAL Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9833410 Reactome Database ID Release 82 9915307 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915307 Reactome R-MMU-8948757 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8948757.1 AKT1 (and possibly AKT2 and AKT3), activated in response to EGF treatment, phosphorylates MKRN1, an E3 ubiquitin ligase, on serine residue S109. AKT-mediated phosphorylation results in stabilization of MKRN1, protecting it from ubiquitination and proteasome-mediated degradation (Lee et al. 2015). 26183061 Pubmed 2015 PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis Lee, Min-Sik Jeong, Man-Hyung Lee, Hyun-Woo Han, Hyun-Ji Ko, Aram Hewitt, SM Kim, Jae-Hoon Chun, Kyung-Hee Chung, Joon-Yong Lee, Cheolju Cho, Hanbyoul Song, Jaewhan Nat Commun 6:7769 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 9926478 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9926478 Reactome R-MMU-198323 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198323.1 Following activation, AKT can phosphorylate an array of target proteins in the cytoplasm, many of which are involved in cell survival control. Phosphorylation of TSC2 feeds positively to the TOR kinase, which, in turn, contributes to AKT activation (positive feedback loop). inferred by electronic annotation IEA GO IEA AKT phosphorylates targets in the nucleus AKT phosphorylates targets in the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.11.1 AKT phosphorylates CREB1 AKT phosphorylates CREB1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29358 1 nucleoplasm GO 0005654 Reactome DB_ID: 9021874 1 UniProt:Q01147 Creb1 Creb1 Creb1 Creb-1 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. Interacts (phosphorylated form) with TOX3 (By similarity). When phosphorylated on Ser-119, binds CREBBP. Interacts with ARRB1. Binds to HIPK2 (By similarity). Interacts with SGK1 (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119 (By similarity). Forms a complex with KMT2A and CREBBP (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 (PubMed:34914893).TISSUE SPECIFICITY Ubiquitously expressed.PTM Phosphorylation of Ser-119 allows CREBBP binding. Stimulated by phosphorylation. Phosphorylated Ser-128 can be detected in the suprachiasmatic nucleus (SCN), the amygdala, the cortex, and the hippocampus but not in the striatum nor in the cerebellum. In the SCN, phosphorylation of Ser-128 and Ser-119 are stimulated by light exposure and submitted to circadian oscillations. In the retina, only phosphorylation of Ser-119 can be detected upon light exposure. Phosphorylation of both Ser-119 and Ser-128 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. 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. Phosphorylation of Ser-271 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP (By similarity). Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion. Phosphorylated by TSSK4 on Ser-119 (By similarity).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 (By similarity).SIMILARITY Belongs to the bZIP family. UniProt Q01147 1 EQUAL 341 EQUAL Reactome DB_ID: 113582 1 Reactome DB_ID: 2976548 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: 9834359 p-T,p-S-AKT [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-T308,S473-AKT1 [nucleoplasm] Reactome Database ID Release 82 9834360 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834360 Reactome Database ID Release 82 9834362 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834362 Reactome R-MMU-199298 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199298.1 AKT phosphorylates CREB (cAMP response element-binding protein) at serine 133 and activates gene expression via a CREB-dependent mechanism, thus promoting cell survival. 9829964 Pubmed 1998 CREB is a regulatory target for the protein kinase Akt/PKB Du, K Montminy, M J Biol Chem 273:32377-9 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT phosphorylates FOXO transcription factors AKT phosphorylates FOXO transcription factors This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9834374 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 Foxo1 [nucleoplasm] Foxo4 [nucleoplasm] Foxo3 [nucleoplasm] UniProt Q9R1E0 UniProt Q9WVH3 UniProt Q9WVH4 Reactome DB_ID: 29358 3 Converted from EntitySet in Reactome Reactome DB_ID: 9834395 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 phospho-Foxo1 [nucleoplasm] phospho-Foxo4 [nucleoplasm] phospho-Foxo3 [nucleoplasm] Reactome DB_ID: 113582 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9834359 Reactome Database ID Release 82 9834397 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834397 Reactome R-MMU-199299 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199299.1 AKT-mediated phosphorylation of Forkhead box (FOX) transcription factors of the FOXO family, FOXO1 (FKHR), FOXO3 (FoxO3a, also known as FKHRL1) and FOXO4 (AFX) contributes to PI3K/AKT signaling-stimulated cell survival and growth. Activated AKT1 phosphorylates FOXO1 on threonine residue T24 and serine residues S256 and S319 (Rena et al. 1999), FOXO3 on threonine residue T32 and serine residues S253 and S315 (Brunet et al. 1999), and FOXO4 on threonine residue T32 and serine residues S197 and S262 (Kops et al. 1999).<br>Based on studies with recombinant mouse Foxo6 expressed in the human embryonic kidney cell line HEK293, FOXO6 has two conserved AKT phosphorylation sites: T26 and S184. Mouse Foxo6 has a third predicted Akt phosphorylation site at the C-terminus, T338, which is not present in other Foxo family members and is not conserved in human FOXO6. T26 and S184 are phosphorylated in response to growth factors known to activate PI3K/AKT signaling, but AKT has not been explicitly identified as the responsible kinase. In contrast to other FOXO family members, FOXO6 remains predominantly nuclear irrespective of growth factor-induced signaling, and only a small portion of phosphorylated FOXO6 may shuttle to the cytosol. Phosphorylation of FOXO6 on putative AKT sites, however, may inhibit binding of FOXO6 to target DNA sites (Jacobs et al. 2003, van der Heide et al. 2005).<br>Protein phosphatase DUSP6 (MKP3) may act to dephosphorylate FOXO1 after AKT-mediated phosphorylation (Rodrigues et al. 2017). 10358075 Pubmed 1999 Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B Rena, G Guo, S Cichy, SC Unterman, TG Cohen, P J Biol Chem 274:17179-83 12857750 Pubmed 2003 FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics Jacobs, Frank M J van der Heide, Lars P Wijchers, Patrick J E C Burbach, J Peter H Hoekman, Marco F M Smidt, Marten P J. Biol. Chem. 278:35959-67 10102273 Pubmed 1999 Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor Brunet, A Bonni, A Zigmond, MJ Lin, MZ Juo, P Hu, LS Anderson, MJ Arden, KC Blenis, J Greenberg, ME Cell 96:857-68 15987244 Pubmed 2005 FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling van der Heide, Lars P Jacobs, Frank M J Burbach, J Peter H Hoekman, Marco F M Smidt, Marten P Biochem. J. 391:623-9 28866049 Pubmed 2017 Overexpression of Mitogen-activated protein kinase phosphatase-3 (MKP-3) reduces FoxO1 phosphorylation in mice hypothalamus Rodrigues, Bárbara de Almeida Kuga, Gabriel Keine Muñoz, Vitor Rosetto Gaspar, Rafael Calais Tavares, Mariana Rosolen Botezelli, José Diego da Silva, Adelino Sanchez Ramos Cintra, Dennys Esper de Moura, Leandro Pereira Simabuco, Fernando Moreira Ropelle, Eduardo Rochete Pauli, José Rodrigo Neurosci. Lett. 659:14-17 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT can phosphorylate RSK AKT can phosphorylate RSK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9834533 1 UniProt:Q9Z1M4 UniProt Q9Z1M4 1 EQUAL 482 EQUAL Reactome DB_ID: 29358 2 Reactome DB_ID: 9834537 1 O-phospho-L-serine at 15 (in Homo sapiens) 15 EQUAL O-phospho-L-serine at 356 (in Homo sapiens) 356 EQUAL 1 EQUAL 482 EQUAL Reactome DB_ID: 113582 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9834359 Reactome Database ID Release 82 9834539 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834539 Reactome R-MMU-199839 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199839.1 Ribosomal protein S6 kinase beta-2 (RSK) activation is a highly conserved mitogenic response, and the activities of RSK are stimulated by multiple serine/threonine phosphorylations by different upstream kinases, one of which is AKT. 10490848 Pubmed 1999 Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); a novel nuclear target of Akt Koh, H Jee, K Lee, B Kim, J Kim, D Yun, YH Kim, JW Choi, HS Chung, J Oncogene 18:5115-9 inferred by electronic annotation IEA GO IEA 2.7.11.1 AKT can phosphorylate NR4A1 (NUR77) AKT can phosphorylate NR4A1 (NUR77) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9834543 1 UniProt:P12813 Nr4a1 UniProt P12813 1 EQUAL 598 EQUAL Reactome DB_ID: 29358 1 Reactome DB_ID: 113582 1 Reactome DB_ID: 9834546 1 O-phospho-L-serine at 351 (in Homo sapiens) 351 EQUAL 1 EQUAL 598 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9834359 Reactome Database ID Release 82 9834548 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834548 Reactome R-MMU-199863 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199863.1 AKT inhibits DNA binding of NUR77 and inhibits its pro-apoptotic function (PMID 11438550). However, the relevance of AKT for NUR77 phosphorylation has recently been questioned: according to recent work, NUR77 is phosphorylated by RSK (and MSK) rather than by AKT (PMID 16223362). 11274386 Pubmed 2001 Akt phosphorylates and regulates the orphan nuclear receptor Nur77 Pekarsky, Y Hallas, C Palamarchuk, A Koval, A Bullrich, F Hirata, Y Bichi, R Letofsky, J Croce, CM Proc Natl Acad Sci U S A 98:3690-4 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 9926506 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9926506 Reactome R-MMU-198693 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198693.1 After translocation into the nucleus, AKT can phosphorylate a number of targets there such as CREB, forkhead transcription factors, SRK and NUR77. inferred by electronic annotation IEA GO IEA Negative regulation of the PI3K/AKT network Negative regulation of the PI3K/AKT network This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 3.1.3.67 PTEN dephosphorylates PIP3 PTEN dephosphorylates PIP3 PI(3,4,5)P3 is dephosphorylated to PI (4,5)P2 by PTEN at the plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 179838 1 Reactome DB_ID: 179856 1 Reactome DB_ID: 29372 1 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9834442 UniProt:O08586 Pten UniProt O08586 2 EQUAL 403 EQUAL GO 0016314 GO molecular function Reactome Database ID Release 82 9834443 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834443 Reactome Database ID Release 82 9834445 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834445 Reactome R-MMU-199456 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199456.1 GO 0051898 GO biological process At the plasma membrane, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase aka phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) (Maehama & Dixon 1998, Myers et al. 1998, Das et al. 2003). The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Myers et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase.<br>Early studies indicated that magnesium ion, Mg2+, was needed for the catalytic activity of PTEN isolated from bovine thymus (Kabuyama et al. 1996). Subsequent studies have shown that PTEN was catalytically active in buffers free of magnesium and magnesium was not detected as part of the PTEN crystal (Lee et al. 1999). 12808147 Pubmed 2003 Membrane-binding and activation mechanism of PTEN Das, S Dixon, JE Cho, W Proc Natl Acad Sci U S A 100:7491-6 9811831 Pubmed 1998 The lipid phosphatase activity of PTEN is critical for its tumor supressor function Myers, MP Pass, I Batty, IH van der Kaay, J Stolarov, JP Hemmings, BA Downes, CP Tonks, NK Wigler, Michael H Proc Natl Acad Sci U S A 95:13513-8 10555148 Pubmed 1999 Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association Lee, Jie-Oh Yang, Haijuan Georgescu, Maria-Magdalena Di Cristofano, Antonio Maehama, Tomohiko Shi, Y Dixon, Jack Pandolfi, Pier Pavletich, Nikola Cell 99:323-34 8681945 Pubmed 1996 Purification and characterization of the phosphatidylinositol-3,4,5-trisphosphate phosphatase in bovine thymus Kabuyama, Y Nakatsu, N Homma, Y Fukui, Y Eur. J. Biochem. 238:350-6 9593664 Pubmed 1998 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate Maehama, T Dixon, JE J Biol Chem 273:13375-8 inferred by electronic annotation IEA GO IEA THEM4 (CTMP) and/or TRIB3 inhibit AKT phosphorylation THEM4 (CTMP) and/or TRIB3 inhibit AKT phosphorylation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9833451 1 Converted from EntitySet in Reactome Reactome DB_ID: 9833482 1 Reactome DB_ID: 9833484 1 Reactome Database ID Release 82 9834438 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834438 Reactome R-MMU-199443 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199443.1 The phosphorylation of membrane-recruited AKT at threonine and serine can be inhibited by direct binding of two different proteins, C-terminal modulator protein (THEM4 i.e. CTMP), which binds to the carboxy-terminal tail of AKT (Maira et al. 2001), or Tribbles homolog 3 (TRIB3), which binds to the catalytic domain of AKT (Du et al. 2003). 11598301 Pubmed 2001 Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane Maira, SM Galetic, I Brazil, DP Kaech, S Ingley, E Thelen, M Hemmings, BA Science 294:374-80 12791994 Pubmed 2003 TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver Du, K Herzig, S Kulkarni, RN Montminy, M Science 300:1574-7 inferred by electronic annotation IEA GO IEA 3.1.3.16 PHLPP dephosphorylates S473 in AKT PHLPP dephosphorylates S473 in AKT This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29356 1 Converted from EntitySet in Reactome Reactome DB_ID: 9833410 1 Converted from EntitySet in Reactome Reactome DB_ID: 9834421 1 p-T-AKT [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-T308-AKT1 [cytosol] Reactome DB_ID: 29372 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9834433 PHLPP (Mn2+ cofactor) [cytosol] PHLPP (Mn2+ cofactor) Converted from EntitySet in Reactome Reactome DB_ID: 9834431 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 Q8CHE4 UniProt Q8BXA7 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 9834433 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834433 Reactome R-MMU-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-MMU-199450.1 GO 0004722 GO molecular function Reactome Database ID Release 82 9834434 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834434 Reactome Database ID Release 82 9834436 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9834436 Reactome R-MMU-199425 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199425.1 The PH domain leucine-rich repeat-containing protein phosphatases, PHLPP1 (Gao et al. 2005) and PHLPP2 (Brognard et al. 2007) can specifically dephosphorylate the serine residue and inactivate AKT. 17386267 Pubmed 2007 PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms Brognard, John Sierecki, Emma Gao, Tianyan Newton, Alexandra C Mol. Cell 25:917-31 15808505 Pubmed 2005 PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth Gao, T Furnari, F Newton, AC Mol Cell 18:13-24 inferred by electronic annotation IEA GO IEA PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.1.68 PI4P is phosphorylated to PI(4,5)P2 by PIP5K1A-C at the plasma membrane PI4P is phosphorylated to PI(4,5)P2 by PIP5K1A-C at the plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 392417 1 1-phosphatidyl-1D-myo-inositol 4-phosphate [ChEBI:17526] 1-phosphatidyl-1D-myo-inositol 4-phosphate ChEBI 17526 Reactome DB_ID: 179856 1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9868069 PIP5K1A-C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Pip5k1c [cytosol] Pip5k1b [cytosol] Pip5k1a [cytosol] UniProt O70161 UniProt P70181 UniProt P70182 GO 0016308 GO molecular function Reactome Database ID Release 82 9868311 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9868311 Reactome Database ID Release 82 9868313 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9868313 Reactome R-MMU-1676082 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1676082.1 At the plasma membrane, phosphatidylinositol-4-phosphate 5-kinase type-1 alpha (PIP5K1A), beta (PIP5K1B), and gamma (PIP5K1C) phosphorylate phosphatidylinositol 4-phosphate (PI4P) to produce phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2).<br><br>The following lists the above proteins with their corresponding literature references: PIP5K1A (Halstead et al. 2006, Zhang et al. 1997), PIP5K1B (Zhang et al. 1997), and PIP5K1C (Di Paolo et al. 2002).<br><br>This reaction is of particular interest because its regulation by small GTPases of the RHO and ARF families, not yet annotated here, ties the process of phosphatidylinositol phosphate biosynthesis to regulation of the actin cytoskeleton and vesicular trafficking, and hence to diverse aspects of cell motility and signalling (Oude Weernink et al. 2004, 2007). 17245604 Pubmed 2007 Phospholipase D signaling: orchestration by PIP2 and small GTPases Oude Weernink, PA López de Jesús, M Schmidt, M Naunyn Schmiedebergs Arch Pharmacol 374:399-411 9211928 Pubmed 1997 Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing phosphatidylinositol signaling molecules Zhang, Xiaoxuan Loijens, JC Boronenkov, IV Parker, GJ Norris, FA Chen, J Thum, O Prestwich, GD Majerus, PW Anderson, RA J Biol Chem 272:17756-61 16979564 Pubmed 2006 A role for PtdIns(4,5)P2 and PIP5Kalpha in regulating stress-induced apoptosis Halstead, JR van Rheenen, J Snel, MH Meeuws, S Mohammed, S D'Santos, CS Heck, AJ Jalink, K Divecha, Nullin Curr Biol 16:1850-6 12422219 Pubmed 2002 Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin Di Paolo, G Pellegrini, L Letinic, K Cestra, G Zoncu, R Voronov, S Chang, S Guo, J Wenk, MR De Camilli, Pietro Nature 420:85-9 15464023 Pubmed 2004 Regulation and cellular roles of phosphoinositide 5-kinases Oude Weernink, PA Schmidt, M Jakobs, KH Eur J Pharmacol 500:87-99 inferred by electronic annotation IEA GO IEA 2.7.1.149 PI5P is phosphorylated to PI(4,5)P2 by PIP4K2 dimers at the plasma membrane PI5P is phosphorylated to PI(4,5)P2 by PIP4K2 dimers at the plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 1806240 1 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) [ChEBI:57795] 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) 1-phosphatidyl-1D-myo-inositol 5-phosphate trianions 1-phosphatidyl-1D-myo-inositol 5-phosphate trianion 2,3-bis(alkanoyloxy)propyl (1R,2R,3R,4R,5S,6R)-2,3,4,6-tetrahydroxy-5-(phosphonatooxy)cyclohexyl phosphate ChEBI 57795 Reactome DB_ID: 179856 1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9868098 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 9868099 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9868099 Reactome Database ID Release 82 9868101 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9868101 Reactome R-MMU-1675776 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1675776.1 At the plasma membrane, phosphatidylinositol-5-phosphate 4-kinase type-2 alpha (PIP4K2A), beta (PIP4K2B) and gamma (PIP4K2C) homodimers and heterodimers (Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015) phosphorylate phosphatidylinositol 5-phosphate (PI5P) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2).<br><br>The following lists the above proteins with their corresponding literature references: PIP4K2A (Rameh et al. 1997, Clarke et al. 2008, Clarke and Irvine 2013), PIP4K2B (Rameh et al. 1997, Clarke and Irvine 2013) and PIP4K2C (Clarke and Irvine 2013, Clarke et al. 2015). 18753295 Pubmed 2008 Localization of phosphatidylinositol phosphate kinase IIgamma in kidney to a membrane trafficking compartment within specialized cells of the nephron Clarke, JH Emson, PC Irvine, RF Am J Physiol Renal Physiol 295:F1422-30 19896968 Pubmed 2010 Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases Clarke, JH Wang, M Irvine, RF Adv Enzyme Regul 50:12-8 23758345 Pubmed 2013 Evolutionarily conserved structural changes in phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) isoforms are responsible for differences in enzyme activity and localization Clarke, Jonathan H Irvine, Robin F Biochem. J. 454:49-57 9367159 Pubmed 1997 A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate Rameh, Lucia Tolias, KF Duckworth, BC Cantley, Lewis C Nature 390:192-6 25495341 Pubmed 2015 The function of phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ) explored using a specific inhibitor that targets the PI5P-binding site Clarke, Jonathan H Giudici, Maria-Luisa Burke, John E Williams, RL Maloney, David J Marugan, Juan Irvine, Robin F Biochem. J. 466:359-67 inferred by electronic annotation IEA GO IEA 3.1.3.16 AKT1 dephosphorylation by PP2A-B56-beta,gamma AKT1 dephosphorylation by PP2A-B56-beta,gamma This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9833402 1 UniProt:P31750 Akt1 Akt1 Rac Akt1 Akt FUNCTION AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:11882383, PubMed:21620960, PubMed:21432781). AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (PubMed:9415393). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (PubMed:11579209). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (PubMed:11994271). AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity (PubMed:22057101). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (PubMed:22057101). AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating the TORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. Also regulates the TORC1 signaling pathway by catalyzing phosphorylation of CASTOR1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1 (By similarity). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (PubMed:10454575). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth (By similarity). AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (PubMed:19778506). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) (PubMed:11282895, PubMed:18288188). AKT mediates the antiapoptotic effects of IGF-I (PubMed:11282895). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (By similarity). May be involved in the regulation of the placental development (PubMed:12783884). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53. Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility. Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation. Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (By similarity). Phosphorylates PCK1 at 'Ser-90', reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor (By similarity). Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity (PubMed:32228865). Acts as a negative regulator of the cGAS-STING pathway by mediating phosphorylation of CGAS during mitosis, leading to its inhibition (PubMed:26440888).ACTIVITY REGULATION Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation.SUBUNIT Interacts with and phosphorylated by PDPK1 (By similarity). Interacts with AGAP2 (isoform 2/PIKE-A); the interaction occurs in the presence of guanine nucleotides. Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with CDKN1B; the interaction phosphorylates CDKN1B promoting 14-3-3 binding and cell-cycle progression. Interacts with MAP3K5 and TRAF6. Interacts with BAD, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with RAF1 (By similarity). Interacts (via the C-terminus) with CCDC88A (via its C-terminus) and THEM4 (via its C-terminus). Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE-binding. Interacts with KCTD20 (PubMed:24156551). Interacts with BTBD10 (PubMed:18160256). Interacts with PA2G4 (By similarity). Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation (By similarity). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (By similarity). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529, PubMed:20189988). Forms a complex with WDFY2 and FOXO1 (PubMed:18388859). Interacts with FAM168A (By similarity). Interacts with SYAP1 (via phosphorylated form and BSD domain); this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1 (PubMed:23300339). Interacts with PKHM3 (PubMed:19028694). Interacts with FKBP5/FKBP51; promoting interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1 (By similarity). Interacts with TMEM175; leading to formation of the lysoK(GF) complex (By similarity).TISSUE SPECIFICITY Widely expressed. Low levels found in liver with slightly higher levels present in thymus and testis.DEVELOPMENTAL STAGE Expressed in trophoblast and vessel endothelial cells of the placenta and in the brain at 14.5 dpc (at protein level).DOMAIN Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction.DOMAIN The AGC-kinase C-terminal mediates interaction with THEM4.PTM O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1 (By similarity). O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site (PubMed:18570920, PubMed:18288188).PTM Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity. Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA. This phosphorylated form localizes to the plasma membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation. Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1. Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1. Ser-473 phosphorylation is enhanced by signaling through activated FLT3. Ser-473 is dephosphorylated by PHLPP (By similarity). Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase. The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase. Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (By similarity).PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation. When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. Also ubiquitinated by TRIM13 leading to its proteasomal degradation. Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome. Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation.PTM Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition (By similarity).PTM Cleavage by caspase-3/CASP3 (PubMed:12124386). Cleaved at the caspase-3 consensus site Asp-462 during apoptosis, resulting in down-regulation of the AKT signaling pathway and decreased cell survival (PubMed:12124386).DISRUPTION PHENOTYPE Show fetal growth impairment and reduced vascularization in the placenta; majority of pups died within 10 days.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain. 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: 9844162 1 1 EQUAL 480 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9906800 PP2A-B56-beta,gamma [cytosol] PP2A-B56-beta,gamma Converted from EntitySet in Reactome Reactome DB_ID: 9825031 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: 9825025 1 PP2A-subunit A [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 9906798 1 PPP2R5B,PPP2R5C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ppp2r5c [cytosol] Ppp2r5b [cytosol] UniProt Q60996 UniProt Q6PD28 Reactome Database ID Release 82 9906800 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9906800 Reactome R-MMU-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-MMU-6811526.1 Reactome Database ID Release 82 9906822 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9906822 Reactome Database ID Release 82 9906824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9906824 Reactome R-MMU-6811504 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6811504.1 The protein phosphatase 2A (PP2A) complex containing a regulatory subunit B56 beta (PPP2R5B) or B56 gamma (PPP2R5C) dephosphorylates activated AKT1 on threonine residue T308 and serine residue S473, thus halting PI3K/AKT signaling (Rocher et al. 2007). Phosphatidylinositol-5-phosphate (PI5P) negatively regulates PP2A-mediated dephosphorylation of AKT1 by promoting, through an unknown mechanism, an inhibitory phosphorylation on tyrosine residue Y307 (Chen et al. 1992) of the catalytic subunit of PP2A (Ramel et al. 2009). 19576174 Pubmed 2009 PtdIns5P protects Akt from dephosphorylation through PP2A inhibition Ramel, Damien Lagarrigue, Frédéric Dupuis-Coronas, Sophie Chicanne, Gaëtan Leslie, Nicholas Gaits-Iacovoni, Frédérique Payrastre, Bernard Tronchère, Hélène Biochem. Biophys. Res. Commun. 387:127-31 1325671 Pubmed 1992 Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation Chen, J Martin, B L Brautigan, D L Science 257:1261-4 17200115 Pubmed 2007 Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity Rocher, Géraldine Letourneux, Claire Lenormand, Philippe Porteu, Françoise J. Biol. Chem. 282:5468-77 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 9906825 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9906825 Reactome DB_ID: 1806240 2.7.10.2 Inhibition of PP2A activity by phosphorylation of the catalytic subunit at tyrosine Y307 Inhibition of PP2A activity by phosphorylation of the catalytic subunit at tyrosine Y307 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 9825033 1 PP2A [cytosol] PP2A Converted from EntitySet in Reactome Reactome DB_ID: 9825031 1 Converted from EntitySet in Reactome Reactome DB_ID: 9825025 1 Converted from EntitySet in Reactome Reactome DB_ID: 9825021 1 PP2A regulatory subunit B56 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 9825033 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9825033 Reactome R-MMU-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-MMU-196206.1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9909766 1 p-Y307-PP2A [cytosol] p-Y307-PP2A Converted from EntitySet in Reactome Reactome DB_ID: 9909764 1 p-Y307-PP2A-catalytic subunit C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 9825025 1 Converted from EntitySet in Reactome Reactome DB_ID: 9825021 1 Reactome Database ID Release 82 9909766 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9909766 Reactome R-MMU-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-MMU-8857938.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9909774 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 9909775 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9909775 Reactome Database ID Release 82 9909777 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9909777 Reactome R-MMU-8857925 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8857925.1 SRC family tyrosine kinases, such as SRC and LCK, as well as receptor tyrosine kinases, such as EGFR and insulin receptor, can phosphorylate the catalytic subunit of serine/threonine protein phosphatase PP2A at tyrosine residue Y307. Phosphorylation at Y307 inhibits the catalytic activity of PP2A. Phosphatidylinositol-5-phosphate (PI5P) positively regulates phosphorylation of the catalytic subunit of PP2A at Y307. inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 82 9909778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9909778 Reactome DB_ID: 1806240 IER3 recruits MAPKs to PP2A-B56-beta,gamma IER3 recruits MAPKs to PP2A-B56-beta,gamma IEX1 recruits ERKs to PP2A This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9906796 1 UniProt:P46694 Ier3 UniProt P46694 1 EQUAL 156 EQUAL Reactome DB_ID: 9906800 1 Converted from EntitySet in Reactome Reactome DB_ID: 9829304 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: 9906802 1 PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimers [cytosol] PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimers Reactome DB_ID: 9906796 1 1 EQUAL 156 EQUAL Reactome DB_ID: 9906800 1 Converted from EntitySet in Reactome Reactome DB_ID: 9829304 1 Reactome Database ID Release 82 9906802 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9906802 Reactome R-MMU-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-MMU-6811477.1 Reactome Database ID Release 82 9906817 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9906817 Reactome R-MMU-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-MMU-6811472.1 IER3 (IEX-1) recruits both an activated MAPK (MAPK1 (ERK2) or MAPK3 (ERK1)) and the protein phosphatase 2A (PP2A) complex containing regulatory subunits B56-beta (PPP2R5B) or B56-gamma (PPP2R5C), through an interaction with the B56 subunit, forming a tripartite complex (Letourneux et al. 2006, Rocher et al. 2007). 16456541 Pubmed 2006 B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK Letourneux, C Rocher, G Porteu, F EMBO J 25:727-38 inferred by electronic annotation IEA GO IEA 2.7.11.1 MAPKs phosphorylate PP2A MAPKs phosphorylate PP2A This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 9906802 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9906796 1 1 EQUAL 156 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9906810 1 p-S368-PPP2R5B,p-S337-PPP2R5C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Ppp2r5c [cytosol] phospho-Ppp2r5b [cytosol] Converted from EntitySet in Reactome Reactome DB_ID: 9829304 1 Reactome DB_ID: 9906812 1 PP2A-A:PP2A-C [cytosol] PP2A-A:PP2A-C Converted from EntitySet in Reactome Reactome DB_ID: 9825031 1 Converted from EntitySet in Reactome Reactome DB_ID: 9825025 1 Reactome Database ID Release 82 9906812 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9906812 Reactome R-MMU-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-MMU-6811485.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9906802 Reactome Database ID Release 82 9906813 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9906813 Reactome Database ID Release 82 9906815 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9906815 Reactome R-MMU-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-MMU-6811454.1 Activated MAPK1 (ERK2) or MAPK3 (ERK1), recruited to the PP2A complex through IER3 (IEX-1), phosphorylate the regulatory subunit PPP2R5B (B56-beta) or PPP2R5C (B56-gamma) of the PP2A complex on serine residue S368 or S337, respectively. ERK-mediated phosphorylation of the PP2A regulatory subunits causes dissociation of the PP2A complex and prevents PP2A-mediated dephosphorylation of AKT1 (Letourneux et al. 2006, Rocher et al. 2007). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 9927524 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9927524 Reactome R-MMU-6811558 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6811558.1 GO 0014066 GO biological process Phosphatidylinositol-5-phosphate (PI5P) may modulate PI3K/AKT signaling in several ways. PI5P is used as a substrate for production of phosphatidylinositol-4,5-bisphosphate, PI(4,5)P2 (Rameh et al. 1997, Clarke et al. 2008, Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015), which serves as a substrate for activated PI3K, resulting in the production of PIP3 (Mandelker et al. 2009, Burke et al. 2011). The majority of PI(4,5)P2 in the cell, however, is produced from the phosphatidylinositol-4-phosphate (PI4P) substrate (Zhang et al. 1997, Di Paolo et al. 2002, Oude Weernink et al. 2004, Halstead et al. 2006, Oude Weernink et al. 2007). PIP3 is necessary for the activating phosphorylation of AKT. AKT1 can be deactivated by the protein phosphatase 2A (PP2A) complex that contains a regulatory subunit B56-beta (PPP2R5B) or B56-gamma (PPP2R5C). PI5P inhibits AKT1 dephosphorylation by PP2A through an unknown mechanism (Ramel et al. 2009). Increased PI5P levels correlate with inhibitory phosphorylation(s) of the PP2A complex. MAPK1 (ERK2) and MAPK3 (ERK1) are involved in inhibitory phosphorylation of PP2A, in a process that involves IER3 (IEX-1) (Letourneux et al. 2006, Rocher et al. 2007). It is uncertain, however, whether PI5P is in any way involved in ERK-mediated phosphorylation of PP2A or if it regulates another PP2A kinase. inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 9926524 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9926524 Reactome R-MMU-199418 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199418.1 The PI3K/AKT network is negatively regulated by phosphatases that dephosphorylate PIP3, thus hampering AKT activation. inferred by electronic annotation IEA GO IEA PDPK1 binds PIP2 PDPK1 binds PIP2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 179856 1 Reactome DB_ID: 9835485 1 1 EQUAL 556 EQUAL Reactome DB_ID: 9876441 1 PDPK1:PIP2 [plasma membrane] PDPK1:PIP2 Reactome DB_ID: 179856 1 Reactome DB_ID: 9822539 1 1 EQUAL 556 EQUAL Reactome Database ID Release 82 9876441 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9876441 Reactome R-MMU-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-MMU-2219520.1 Reactome Database ID Release 82 9876443 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9876443 Reactome R-MMU-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-MMU-2219524.1 PDPK1 (PDK1) possesses low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane, in the absence of PI3K activity (Currie et al. 1999). inferred by electronic annotation IEA GO IEA PTEN Regulation PTEN Regulation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Regulation of PTEN gene transcription Regulation of PTEN gene transcription This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> SALL4 recruits NuRD to PTEN gene SALL4 recruits NuRD to PTEN gene This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9914986 1 SALL4:PTEN gene [nucleoplasm] SALL4:PTEN gene Reactome DB_ID: 9914984 1 Ghost homologue of PTEN gene [nucleoplasm] Ghost homologue of PTEN gene Reactome DB_ID: 9879408 1 UniProt:Q8BX22 Sall4 UniProt Q8BX22 1 EQUAL 1053 EQUAL Reactome Database ID Release 82 9914986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9914986 Reactome R-MMU-8943729 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8943729.1 Reactome DB_ID: 9819770 1 NuRD complex [nucleoplasm] NuRD complex Reactome DB_ID: 9006136 1 Hdac1:Hdac2 [nucleoplasm] Hdac1:Hdac2 Reactome DB_ID: 573366 1 UniProt:P70288 Hdac2 Hdac2 Hdac2 Yy1bp FUNCTION Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:18754010). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:18754010). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:18754010). Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR (By similarity). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (PubMed:17707228). Also deacetylates non-histone targets: deacetylates TSHZ3, thereby regulating its transcriptional repressor activity (By similarity). May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation (PubMed:15226430). Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A (PubMed:20071335). In addition to protein deacetylase activity, also acts as protein-lysine deacylase by recognizing other acyl groups: catalyzes removal of (2E)-butenoyl (crotonyl) and 2-hydroxyisobutanoyl (2-hydroxyisobutyryl) acyl groups from lysine residues, leading to protein decrotonylation and de-2-hydroxyisobutyrylation, respectively (PubMed:30279482).SUBUNIT Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7 (By similarity). The core complex associates with MTA2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex (By similarity). Component of a RCOR/GFI/KDM1A/HDAC complex (PubMed:17707228). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B, KDM1A, RCOR1 and PHF21A (By similarity). The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (By similarity). Part of a complex containing the core histones H2A, H2B, H3 and H4, DEK and unphosphorylated DAXX (By similarity). Part of a complex containing ATR and CHD4 (By similarity). Forms a heterologous complex at least with YY1 (By similarity). Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1 (By similarity). Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3, ARID4B, HDAC1 and HDAC2 (By similarity). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (By similarity). Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2 (By similarity). Component of a histone deacetylase complex containing DNTTIP1, ZNF541, HDAC1 and HDAC2 (By similarity). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC1 (By similarity). Interacts with SPHK2 (By similarity). Interacts directly with GFI1 and GFI1B (PubMed:17707228). Interacts with SNW1, HDAC7, PRDM6, SAP30, SETDB1 and SUV39H1 (PubMed:11788710, PubMed:12398767, PubMed:10984530, PubMed:9702189, PubMed:16537907). Interacts with the MACROH2A1 (via the non-histone region) (PubMed:16107708). Interacts with ATR, CBFA2T3, DNMT1, SMARCAD1, MINT, HDAC10, HCFC1, NRIP1, KDM4A and PELP1 (PubMed:11533236). Interacts with CHFR and SAP30L (By similarity). Interacts (CK2 phosphorylated form) with SP3 (By similarity). Interacts with TSHZ3 (via its N-terminus) (By similarity). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (By similarity). Interacts with PIMREG (By similarity). Interacts with BCL6 (non-acetylated form) (By similarity). Interacts with CRY1, INSM1 and ZNF431 (PubMed:21177534, PubMed:22391310, PubMed:24227653, PubMed:15226430). Interacts with NACC2 (By similarity). Interacts with MTA1, with a preference for sumoylated MTA1 (By similarity). Interacts with SIX3 (PubMed:17666527). Interacts with BEND3 (By similarity). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (By similarity). Interacts with PWWP2B (PubMed:34180153).PTM S-nitrosylated by GAPDH. In neurons, S-nitrosylation at Cys-262 and Cys-274 does not affect enzyme activity, but induces HDAC2 release from chromatin. This in turn increases acetylation of histones surrounding neurotrophin-dependent gene promoters and promotes their transcription. In embryonic cortical neurons, S-Nitrosylation regulates dendritic growth and branching.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily.CAUTION Was originally thought to be S-nitrosylated and to interact with MTA1 (PubMed:20519513). However, this work was later retracted (PubMed:28314777). Nevertheless, other publications demonstrate that it is S-nitrosylated and there are several publications in the human ortholog demonstrating its interaction with MTA1 (PubMed:18754010, PubMed:20972425). UniProt P70288 1 EQUAL 488 EQUAL Reactome DB_ID: 573340 1 UniProt:O09106 Hdac1 Hdac1 Hdac1 FUNCTION Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:10615135, PubMed:15542849, PubMed:21960634, PubMed:30279482). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:10615135, PubMed:15542849, PubMed:21960634). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:10615135, PubMed:21960634). Also functions as deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3 and TSHZ3 (By similarity). Deacetylates SP proteins, SP1 and SP3, and regulates their function (By similarity). Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons (By similarity). Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation (By similarity). Deacetylates TSHZ3 and regulates its transcriptional repressor activity (By similarity). Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B (By similarity). Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity (By similarity). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (PubMed:17707228). Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer (PubMed:15226430, PubMed:24736997). Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation (PubMed:15226430). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones (PubMed:30279482).SUBUNIT Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7 (By similarity). The core complex associates with MTA2, MBD2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex (PubMed:11909966, PubMed:9702189). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST and PHF21A/BHC80 (By similarity). The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (By similarity). Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3/SAP45, ARID4B/SAP180, HDAC1 and HDAC2 (By similarity). Found in a trimeric complex with APBB1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3 (By similarity). Interacts with TSHZ3 (via N-terminus); the interaction is direct (By similarity). Component of a RCOR/GFI/KDM1A/HDAC complex (PubMed:17707228). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (By similarity). Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2 (By similarity). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A (PubMed:24413057). Associates with the 9-1-1 complex; interacts with HUS1 (By similarity). Found in a complex with DNMT3A and HDAC7 (PubMed:10984530, PubMed:12616525). Interacts with the non-histone region of MACROH2A1 (PubMed:16107708). Interacts with TRIM28; the interaction recruits HDAC1 to E2F1 and inhibits its acetylation (By similarity). Interacts with SP1; the interaction deacetylates SP1 and regulates its transcriptional activity (By similarity). Interacts with SP3; the interaction deacetylates SP3 and regulates its transcriptional activity (By similarity). In vitro, C(18) ceramides increase this interaction and the subsequent SP3 deacetylation and SP3-mediated repression of the TERT promoter (By similarity). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (By similarity). Interacts with C10orf90/FATS (via its N-terminal); the interaction prevents binding of HDAC1 to CDKN1A/p21 and facilitates the acetylation and stabilization of CDKN1A/p21 (PubMed:20154723). Interacts with CDKN1A/p21 (PubMed:20154723). Interacts with CDK5 complexed to CDK5R1 (p25) (PubMed:20154723). Interacts directly with GFI1 and GFI1B (PubMed:17707228). Interacts with NR1D2 (via C-terminus) (By similarity). Interacts with TSC22D3 isoform 1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity (PubMed:20124407). Interacts with BAZ2A/TIP5, BANP, BCL6, BCOR, BHLHE40/DEC1, BRMS1, BRMS1L, CBFA2T3, CHFR, CIART, CRY1, DAXX, DDIT3/CHOP, DDX5, E4F1, EP300, HCFC1, HDAC9, INSM1, NFE4, NR4A2/NURR1, MIER1, KDM4A, KDM5B, KLF1, MINT, DNMT1, NRIP1, PCAF, PHB2, PRDM6, PRDM16, RB1, RERE, SAMSN1, SAP30L, SETDB1, SMAD3, SMARCAD1, SMARCA4/BRG1, SMYD2, SUV39H1, TGIF, TGIF2, TRAF6, UHRF1, UHRF2, ZMYND15, ZNF431 and ZNF541 (PubMed:14645126, PubMed:11022042, PubMed:12198165, PubMed:12398767, PubMed:11533236, PubMed:15711539, PubMed:16611996, PubMed:11788710, PubMed:10615135, PubMed:16805913, PubMed:24736997, PubMed:19144721, PubMed:18849567, PubMed:24227653, PubMed:20675388, PubMed:20478393, PubMed:22242125, PubMed:15060175, PubMed:16166625, PubMed:16537907, PubMed:16085498, PubMed:15140878, PubMed:15542849, PubMed:15226430, PubMed:21177534). Interacts with KDM5A; this interaction impairs histone deacetylation (PubMed:21960634). Interacts with DNTTIP1 (By similarity). Identified in a histone deacetylase complex that contains DNTTIP1, HDAC1 and MIDEAS; this complex assembles into a tetramer that contains four copies of each protein chain (By similarity). Interacts with CCAR2 (By similarity). Interacts with PPHLN1 (By similarity). Found in a complex with YY1, SIN3A and GON4L (PubMed:21454521). Interacts with CHD4 (By similarity). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (PubMed:28554894). Interacts with SIN3A (PubMed:28554894). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (By similarity). Interacts with ZBTB7A (By similarity). Interacts with SMAD4; positively regulated by ZBTB7A (By similarity). Interacts with PACS2 (By similarity). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC2 (By similarity). Interacts with ZNF638 (By similarity). Interacts with SPHK2. Interacts with ERCC6 (By similarity). Interacts with NSD2 (PubMed:19483677). Interacts with SMYD4 (via MYND-type zinc finger) (By similarity). Interacts with isoform 1 and isoform 3 of PWWP2A in a MTA1-dependent manner (PubMed:30228260). Interacts with PWWP2B (PubMed:30228260, PubMed:34180153). Interacts with ZNF516 and BRCC3; these interactions are enhanced in the presence of PWWP2B (PubMed:34180153). Interacts with SANBR (via the BTB domain) (PubMed:33831416).TISSUE SPECIFICITY Widely expressed with higher levels in thymus and testis and lower levels in liver. Present in muscle (at protein level).INDUCTION By interleukin-2.PTM Sumoylated on Lys-444 and Lys-476; which promotes enzymatic activity. Desumoylated by SENP1.PTM Phosphorylation on Ser-421 and Ser-423 promotes enzymatic activity and interactions with NuRD and SIN3 complexes. Phosphorylated by CDK5.PTM Ubiquitinated by CHFR and KCTD11, leading to its degradation by the proteasome.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt O09106 1 EQUAL 482 EQUAL Reactome Database ID Release 82 9006136 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9006136 Reactome R-MMU-9006136 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9006136.1 Reactome DB_ID: 9819751 1 UniProt:Q9Z2D8 Mbd3 Mbd3 Mbd3 FUNCTION Acts as transcriptional repressor and plays a role in gene silencing. Does not bind DNA by itself. Binds to DNA with a preference for sites containing methylated CpG dinucleotides (in vitro). Binds to a lesser degree DNA containing unmethylated CpG dinucleotides (By similarity). Recruits histone deacetylases and DNA methyltransferases.SUBUNIT Heterodimer with MBD2. Part of the NuRD and the MeCP1 complex. Interacts with BCL6, HDAC1, MTA2, DNMT1, p66-alpha and p66-beta (By similarity). Does not interact with PWWP2A and PWWP2B (PubMed:30228260, PubMed:30327463).TISSUE SPECIFICITY Highly expressed in brain, heart, kidney, liver, lung, skeletal muscle, spleen and testis. Detected at lower levels in embryonic stem cells. UniProt Q9Z2D8 1 EQUAL 291 EQUAL Reactome DB_ID: 9819740 1 UniProt:Q60973 Rbbp7 Rbbp7 Rbap46 Rbbp7 FUNCTION Core histone-binding subunit that may target chromatin remodeling factors, histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the type B histone acetyltransferase (HAT) complex, which is required for chromatin assembly following DNA replication; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; and the PRC2/EED-EZH2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex (By similarity).SUBUNIT Binds directly to helix 1 of the histone fold of histone H4, a region that is not accessible when H4 is in chromatin. Subunit of the type B histone acetyltransferase (HAT) complex, composed of RBBP7 and HAT1. Subunit of the core histone deacetylase (HDAC) complex, which is composed of HDAC1, HDAC2, RBBP4 and RBBP7. The core HDAC complex associates with SIN3A, ARID4B/SAP180, SAP18, SAP30, SAP130, SUDS3/SAP45 and possibly ARID4A/RBP1 and ING1 to form the SIN3 HDAC complex. The core HDAC complex may also associate with MTA2, MBD3, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylase complex (the NuRD complex). The NuRD complex may also interact with MBD3L1 and MBD3L2. Interacts with MTA1. Subunit of the PRC2/EED-EZH2 complex, which is composed of at least EED, EZH2, RBBP4, RBBP7 and SUZ12. The PRC2/EED-EZH2 complex may also associate with HDAC1. Component of the NURF-1 ISWI chromatin remodeling complex (also called the nucleosome-remodeling factor (NURF) complex) at least composed of SMARCA1; BPTF; RBBP4 and RBBP7 (By similarity). Within the complex interacts with SMARCA1 (By similarity). Interacts with the viral protein-binding domain of the retinoblastoma protein (RB1). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP. Interacts with CENPA (By similarity). Interacts with BRCA1 (By similarity). Interacts with HDAC7 (PubMed:10984530). Interacts with SUV39H1 (PubMed:11788710). Interacts with PWWP2B (PubMed:34180153).TISSUE SPECIFICITY Higher levels in brain, thymus, lung, spleen, kidney, testis, and ovary/uterus; lower levels in heart, liver, and muscle.SIMILARITY Belongs to the WD repeat RBAP46/RBAP48/MSI1 family. UniProt Q60973 2 EQUAL 425 EQUAL Reactome DB_ID: 573325 1 UniProt:Q60972 Rbbp4 Rbbp4 Rbap48 Rbbp4 FUNCTION Core histone-binding subunit that may target chromatin assembly factors, chromatin remodeling factors and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the chromatin assembly factor 1 (CAF-1) complex, which is required for chromatin assembly following DNA replication and DNA repair; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; the PRC2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex.SUBUNIT Binds directly to helix 1 of the histone fold of histone H4, a region that is not accessible when H4 is in chromatin. Subunit of the chromatin assembly factor 1 (CAF-1) complex, which is composed of RBBP4, CHAF1B and CHAF1A (By similarity). Subunit of the core histone deacetylase (HDAC) complex, which is composed of HDAC1, HDAC2, RBBP4 and RBBP7 (By similarity). The core HDAC complex associates with SIN3A, ARID4B/SAP180, SAP18, SAP30, SAP130, SUDS3/SAP45 and possibly ARID4A/RBP1 and ING1 to form the SIN3 HDAC complex (Probable). The core HDAC complex may also associate with MTA2, MBD3, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylase complex (the NuRD complex) (By similarity). The NuRD complex may also interact with MBD3L1 and MBD3L2 (By similarity). Interacts with MTA1 (By similarity). Component of the PRC2 complex, which consists of the core subunits EED, EZH1 or EZH2, SUZ12, and RBBP4, and various combinations of accessory subunits including AEBP2, JARID2, PHF19, MTF2 and EPOP (PubMed:19026780). Forms a monomeric PRC2.2 (class 2) complex consisting of at least SUZ12, RBBP4, AEBP2 and JARID2 (By similarity). Forms a dimeric PRC2.1 (class 1, PRC-PCL) complex consisting of at least SUZ12, RBBP4, and PHF19; PHF19 stabilizes the dimeric structure which enhances PRC2 interaction with chromatin (By similarity). Component of the NURF-1 ISWI chromatin remodeling complex (also called the nucleosome-remodeling factor (NURF) complex) at least composed of SMARCA1; BPTF; RBBP4 and RBBP7 (PubMed:10866654). Within the complex interacts with SMARCA1 (By similarity). Interacts with the ISWI chromatin remodeling complex component SMARCA5; the interaction is direct (By similarity). Interacts with SUV39H1 and HDAC7 (PubMed:10984530, PubMed:11788710). Interacts with the viral protein-binding domain of the retinoblastoma protein (RB1) (By similarity). Interacts with SPEN/MINT (By similarity). Interacts with BRCA1 (By similarity). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP (By similarity). Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2 (By similarity). The complex exists in quiescent cells where it represses cell cycle-dependent genes (By similarity). It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2 (By similarity). Interacts with PHF6 (By similarity). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (PubMed:28554894). Interacts with ERCC6 (By similarity). Interacts with ZNF827; the interaction is direct and recruits RBBP4 to telomeres (By similarity). Interacts with ARMC12 (via ARM domains) (By similarity). Interacts with PWWP2B (PubMed:34180153).TISSUE SPECIFICITY Higher levels in brain, thymus, lung, spleen, kidney, testis, and ovary/uterus; lower levels in heart, liver, and muscle.SIMILARITY Belongs to the WD repeat RBAP46/RBAP48/MSI1 family. UniProt Q60972 2 EQUAL 425 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9819758 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 Mta3 [nucleoplasm] Mta1 [nucleoplasm] Mta2 [nucleoplasm] UniProt Q924K8 UniProt Q8K4B0 UniProt Q9R190 Converted from EntitySet in Reactome Reactome DB_ID: 9819748 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 Q6PDQ2 UniProt B1AR17 Converted from EntitySet in Reactome Reactome DB_ID: 9819768 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 9819770 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9819770 Reactome R-MMU-4657018 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-4657018.1 Reactome DB_ID: 9914990 1 SALL4:NuRD:PTEN gene [nucleoplasm] SALL4:NuRD:PTEN gene Reactome DB_ID: 9914984 1 Reactome DB_ID: 9914988 1 SALL4:NuRD [nucleoplasm] SALL4:NuRD Reactome DB_ID: 9879408 1 1 EQUAL 1053 EQUAL Reactome DB_ID: 9819770 1 Reactome Database ID Release 82 9914988 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9914988 Reactome R-MMU-8943778 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8943778.1 Reactome Database ID Release 82 9914990 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9914990 Reactome R-MMU-8943781 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8943781.1 Reactome Database ID Release 82 9914992 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9914992 Reactome R-MMU-8943780 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8943780.1 SALL4 recruits the transcriptional repressor complex NuRD, containing histone deacetylases HDAC1 and HDAC2, to the PTEN gene promoter (Lu et al 2009, Gao et al. 2013). SALL4 may also recruit DNA methyltransferases (DNMTs) to the PTEN promoter (Yang et al. 2012). 22128185 Pubmed 2012 Stem cell gene SALL4 suppresses transcription through recruitment of DNA methyltransferases Yang, Jianchang Corsello, Tyler R Ma, Yupo J. Biol. Chem. 287:1996-2005 19440552 Pubmed 2009 Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex Lu, J Jeong, HW Kong, N Yang, Y Carroll, J Luo, HR Silberstein, LE Yupoma, LE Chai, L PLoS One 4:e5577 23287862 Pubmed 2013 Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex Gao, Chong Dimitrov, Todor Yong, Kol Jia Tatetsu, Hiro Jeong, Ha-Won Luo, Hongbo R Bradner, James E Tenen, Daniel G Chai, Li Blood 121:1413-21 inferred by electronic annotation IEA GO IEA MECOM (EVI1) recruits polycomb repressor complexes (PRCs) to the PTEN gene promoter MECOM (EVI1) recruits polycomb repressor complexes (PRCs) to the PTEN gene promoter This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9914998 1 MECOM:PTEN gene [nucleoplasm] MECOM:PTEN gene Reactome DB_ID: 9914984 1 Reactome DB_ID: 9914994 1 UniProt:P14404 Mecom UniProt P14404 1 EQUAL 1051 EQUAL Reactome Database ID Release 82 9914998 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9914998 Reactome R-MMU-8943810 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8943810.1 Converted from EntitySet in Reactome Reactome DB_ID: 9914996 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: 9915002 1 MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core):PTEN gene Reactome DB_ID: 9914984 1 Reactome DB_ID: 9915000 1 MECOM:(PRC1.4,PRC2 (EZH2) core) [nucleoplasm] MECOM:(PRC1.4,PRC2 (EZH2) core) Converted from EntitySet in Reactome Reactome DB_ID: 9914996 1 Reactome DB_ID: 9914994 1 1 EQUAL 1051 EQUAL Reactome Database ID Release 82 9915000 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915000 Reactome R-MMU-8943820 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8943820.1 Reactome Database ID Release 82 9915002 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915002 Reactome R-MMU-8943821 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8943821.1 Reactome Database ID Release 82 9915004 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915004 Reactome R-MMU-8943817 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8943817.1 The transcription factor MECOM (EVI1) can associate with the polycomb repressor complexes (PRCs) and recruit them to the promoter of the PTEN gene (Song et al. 2009). Both the BMI1-containing PRC, supposedly PRC1.4, and the EZH2-containing PRC2 complex are recruited to the PTEN promoter, resulting in transcriptional silencing of the PTEN gene (Song et al. 2009, Yoshimi et al. 2011). Since the exact composition of the EZH2-containing PRC2 at the PTEN promoter is not known, the core EZH2-PRC2 complex is shown. 21289308 Pubmed 2011 Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins Yoshimi, Akihide Goyama, Susumu Watanabe-Okochi, Naoko Yoshiki, Yumiko Nannya, Yasuhito Nitta, Eriko Arai, Shunya Sato, Tomohiko Shimabe, Munetake Nakagawa, Masahiro Imai, Yoichi Kitamura, Toshio Kurokawa, Mineo Blood 117:3617-28 19884659 Pubmed 2009 The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells Song, Li-Bing Li, J Liao, Wen-Ting Feng, Yan Yu, Chun-Ping Hu, Li-Juan Kong, Qing-Li Xu, Li-Hua Zhang, Xing Liu, Wan-Li Li, Man-Zhi Zhang, L Kang, Tie-Bang Fu, Li-Wu Huang, Wen-Lin Xia, Yun-Fei Tsao, Sai Wah Li, Mengfeng Band, Vimla Band, Hamid Shi, Qing-Hua Zeng, Yi-Xin Zeng, Mu-Sheng J. Clin. Invest. 119:3626-36 inferred by electronic annotation IEA GO IEA 2.7.11.1 mTORC1 phosphorylates MAF1 mTORC1 phosphorylates MAF1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 3 Reactome DB_ID: 9915107 1 UniProt:Q9D0U6 Maf1 UniProt Q9D0U6 1 EQUAL 256 EQUAL Reactome DB_ID: 9915112 1 O-phospho-L-serine at 60 (in Homo sapiens) 60 EQUAL O-phospho-L-serine at 68 (in Homo sapiens) 68 EQUAL O-phospho-L-serine at 75 (in Homo sapiens) 75 EQUAL 1 EQUAL 256 EQUAL Reactome DB_ID: 29370 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9827148 lysosomal membrane GO 0005765 Active mTORC1 complex [lysosomal membrane] Active mTORC1 complex Reactome DB_ID: 9827068 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: 9827064 1 UniProt:Q921J2 UniProt Q921J2 1 EQUAL 181 EQUAL Reactome Database ID Release 82 9827068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827068 Reactome R-MMU-165189 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-165189.1 Reactome DB_ID: 9827146 1 mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 [lysosomal membrane] mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Reactome DB_ID: 9827144 1 Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 [lysosomal membrane] Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9 Reactome DB_ID: 9827088 1 UniProt:Q8BGD6 Slc38a9 UniProt Q8BGD6 1 EQUAL 561 EQUAL Reactome DB_ID: 9827142 1 Ragulator:RagA,B:GTP:RagC,D:GDP [lysosomal membrane] Ragulator:RagA,B:GTP:RagC,D:GDP Reactome DB_ID: 9827140 1 RagA,B:GTP:RagC,D:GDP [cytosol] RagA,B:GTP:RagC,D:GDP Converted from EntitySet in Reactome Reactome DB_ID: 9827124 1 RRAGA, RRAGB:GTP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 9827138 1 RRAGC,RRAGD:GDP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 9827140 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827140 Reactome R-MMU-5653945 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5653945.1 Reactome DB_ID: 9827110 1 Ragulator [lysosomal membrane] Ragulator Reactome DB_ID: 9827100 1 UniProt:O88653 Lamtor3 UniProt O88653 1 EQUAL 124 EQUAL Reactome DB_ID: 9827096 1 UniProt:Q9JHS3 Lamtor2 UniProt Q9JHS3 1 EQUAL 125 EQUAL Reactome DB_ID: 9827108 1 UniProt:Q9D1L9 Lamtor5 UniProt Q9D1L9 1 EQUAL 91 EQUAL Reactome DB_ID: 9827104 1 UniProt:Q8CF66 Lamtor4 UniProt Q8CF66 1 EQUAL 99 EQUAL Reactome DB_ID: 9827092 1 UniProt:Q9CQ22 Lamtor1 UniProt Q9CQ22 2 EQUAL 161 EQUAL Reactome Database ID Release 82 9827110 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827110 Reactome R-MMU-5653921 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5653921.1 Reactome Database ID Release 82 9827142 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827142 Reactome R-MMU-5653979 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5653979.1 Reactome Database ID Release 82 9827144 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827144 Reactome R-MMU-8952725 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8952725.1 Reactome DB_ID: 9827084 1 mTORC1 [cytosol] mTORC1 Reactome DB_ID: 9827082 1 UniProt:Q8K4Q0 Rptor UniProt Q8K4Q0 1 EQUAL 1335 EQUAL Reactome DB_ID: 9827078 1 1 EQUAL 2549 EQUAL Reactome DB_ID: 9827074 1 1 EQUAL 326 EQUAL Reactome Database ID Release 82 9827084 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827084 Reactome R-MMU-377400 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-377400.1 Reactome Database ID Release 82 9827146 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827146 Reactome R-MMU-5653972 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5653972.1 Reactome Database ID Release 82 9827148 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827148 Reactome R-MMU-165678 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-165678.1 Reactome Database ID Release 82 9915113 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915113 Reactome Database ID Release 82 9915115 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915115 Reactome R-MMU-8944454 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8944454.1 Activated mTORC1 complex phosphorylates the transcription factor MAF1 on serine residues S60, S68 and S75 (Shor et al. 2010, Michels et al. 2010). mTORC1-mediated phosphorylation of MAF1 inhibits translocation of MAF1 to the nucleus (Shor et al. 2010). 20233713 Pubmed 2010 Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells Shor, Boris Wu, Jiang Shakey, Quazi Toral-Barza, Lourdes Shi, Celine Follettie, Max Yu, Ker J. Biol. Chem. 285:15380-92 20516213 Pubmed 2010 mTORC1 directly phosphorylates and regulates human MAF1 Michels, Annemieke A Robitaille, Aaron M Buczynski-Ruchonnet, Diane Hodroj, Wassim Reina, Jaime H Hall, Michael N Hernandez, Nouria Mol. Cell. Biol. 30:3749-57 inferred by electronic annotation IEA GO IEA MAF1 translocates to the nucleus MAF1 translocates to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9915107 1 1 EQUAL 256 EQUAL Reactome DB_ID: 9915105 1 1 EQUAL 256 EQUAL Reactome Database ID Release 82 9915117 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915117 Reactome R-MMU-8944457 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8944457.1 Phosphorylation of MAF1 by the activated mTORC1 complex inhibits translocation of MAF1 to the nucleus, and hence its transcriptional activity, but the mechanism has not been elucidated (Shor et al. 2010). inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 9915118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915118 Reactome DB_ID: 9827148 Reactome Database ID Release 82 9928294 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9928294 Reactome R-MMU-8943724 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8943724.1 Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016). 11378386 Pubmed 2001 Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN Patel, L Pass, I Coxon, P Downes, C P Smith, S A MacPhee, C H Curr. Biol. 11:764-8 16702404 Pubmed 2006 Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1 Zhang, Chun-Li Zou, Yuhua Yu, Ruth T Gage, Fred H Evans, Ronald M Genes Dev. 20:1308-20 18172008 Pubmed 2008 Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis Escrivà, Maria Peiró, Sandra Herranz, Nicolás Villagrasa, Patricia Dave, Natàlia Montserrat-Sentís, Bàrbara Murray, Stephen A Francí, Clara Gridley, T Virtanen, Ismo García de Herreros, Antonio Mol. Cell. Biol. 28:1528-40 17974977 Pubmed 2007 Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras Vasudevan, Krishna Murthi Burikhanov, Ravshan Goswami, Anindya Rangnekar, Vivek M Cancer Res. 67:10343-50 11545734 Pubmed 2001 Regulation of PTEN transcription by p53 Stambolic, V MacPherson, D Sas, D Lin, Y Snow, B Jang, Y Benchimol, S Mak, T W Mol. Cell 8:317-25 11781575 Pubmed 2001 The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling Virolle, T Adamson, Eileen D Baron, V Birle, D Mercola, D Mustelin, T de Belle, I Nat. Cell Biol. 3:1124-8 18487508 Pubmed 2008 SALL4 is a key regulator of survival and apoptosis in human leukemic cells Yang, Jianchang Chai, Li Gao, Chong Fowles, Taylor C Alipio, Zaida Dang, Hien Xu, Dan Fink, Louis M Ward, David C Ma, Yupo Blood 112:805-13 26910647 Pubmed 2016 MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription Li, Yue Tsang, Chi Kwan Wang, Suihai Li, Xiao-Xing Yang, Yang Fu, Liwu Huang, Wenlin Li, Ming Wang, Hui-Yun Zheng, X F Steven Hepatology 63:1928-42 16418168 Pubmed 2006 Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells Shen, Ying H Zhang, Lin Gan, Yehua Wang, Xinwen Wang, Jian LeMaire, Scott A Coselli, Joseph S Wang, Xing Li J. Biol. Chem. 281:7727-36 25728608 Pubmed 2015 SLUG is a direct transcriptional repressor of PTEN tumor suppressor Uygur, Berna Abramo, Katrina Leikina, Evgenia Vary, Calvin Liaw, Lucy Wu, Wen-Shu Prostate 75:907-16 inferred by electronic annotation IEA GO IEA Regulation of PTEN localization Regulation of PTEN localization This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PTEN undergoes monoubiquitination PTEN undergoes monoubiquitination This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9834442 1 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9816098 1 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Rps27a [cytosol] Ubiquitin (Ubc 6) [cytosol] Ubiquitin (Ubc 3) [cytosol] Ubiquitin (Ubc 2) [cytosol] Ubiquitin (Ubc 4) [cytosol] Ubiquitin related 1 (Ubc r1) [cytosol] Ubiquitin (Ubb 1) [cytosol] Ubiquitin (Pps27a) [cytosol] Ubiquitin (Ubc 1) [cytosol] Ubiquitin (Ubc 5) [cytosol] Ubiquitin (Uba52) [cytosol] Ubiquitin (Ubc 7) [cytosol] Ubiquitin (Ubc 8) [cytosol] UniProt P62983 UniProt P0CG50 UniProt P0CG49 UniProt P62984 Reactome DB_ID: 9904528 1 ubiquitinylated lysine (Ub [cytosol]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine [MOD:01148] ubiquitinylated lysine (Ub [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9904536 XIAP,NEDD4 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0061630 GO molecular function Reactome Database ID Release 82 9904537 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9904537 Reactome Database ID Release 82 9904539 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9904539 Reactome R-MMU-6807106 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6807106.1 When present at low levels in the cell, the E3 ubiquitin ligase XIAP monoubiquitinates PTEN (Van Themsche et al. 2009). NEDD4 (NEDD4-1) can also monoubiquitinate PTEN (Trotman et al. 2007). Monoubiquitination of PTEN on at least lysine residues K13 and K289 causes translocation of PTEN from the cytosol to the nucleus (Trotman et al. 2007, Van Themsche et al. 2009). 17218261 Pubmed 2007 Ubiquitination regulates PTEN nuclear import and tumor suppression Trotman, Lloyd C Wang, Xinjiang Alimonti, Andrea Chen, Zhenbang Teruya-Feldstein, Julie Yang, Haijuan Pavletich, Nikola P Carver, Brett S Cordon-Cardo, Carlos Erdjument-Bromage, H Tempst, P Chi, Sung-Gil Kim, Hyo-Jong Misteli, Tom Jiang, Xuejun Pandolfi, Pier Paolo Cell 128:141-56 19473982 Pubmed 2009 X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization Van Themsche, Céline Leblanc, Valérie Parent, Sophie Asselin, Eric J. Biol. Chem. 284:20462-6 inferred by electronic annotation IEA GO IEA Monoubiquitinated PTEN translocates to the nucleus Monoubiquitinated PTEN translocates to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9904528 1 ubiquitinylated lysine (Ub [cytosol]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine (Ub [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 9904532 1 ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 82 9904534 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9904534 Reactome R-MMU-6807105 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6807105.1 Monoubiquitinated PTEN translocates to the nucleus. Lysine residues K13 and K289 of PTEN are important monoubiquitination targets and their mutation abrogates PTEN nuclear localization (Trotman et al. 2007). inferred by electronic annotation IEA GO IEA 3.4.19.12 USP7 deubiquitinates monoubiquitinated PTEN USP7 deubiquitinates monoubiquitinated PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9904532 1 ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 13 (in Homo sapiens) 13 EQUAL ubiquitinylated lysine (ubiquitin [nucleoplasm]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 113518 1 Converted from EntitySet in Reactome Reactome DB_ID: 9815689 2 Ub [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ubiquitin (Ubc 4) [nucleoplasm] Ubiquitin (Ubb 1) [nucleoplasm] Ubiquitin (Ubc 7) [nucleoplasm] Ubiquitin (Ubc 1) [nucleoplasm] Ubiquitin (Ubc 3) [nucleoplasm] Ubiquitin (Ubc 6) [nucleoplasm] Ubiquitin related 1 (Ubc r1) [nucleoplasm] Ubiquitin (Ubc 5) [nucleoplasm] Ubiquitin (Ubc 8) [nucleoplasm] Rps27a [nucleoplasm] Ubiquitin (Ubc 2) [nucleoplasm] Ubiquitin (Pps27a) [nucleoplasm] Ubiquitin (Uba52) [nucleoplasm] Reactome DB_ID: 9894760 1 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9880246 UniProt:Q6A4J8 Usp7 UniProt Q6A4J8 1 EQUAL 1102 EQUAL GO 0004843 GO molecular function Reactome Database ID Release 82 9880275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9880275 Reactome Database ID Release 82 9904541 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9904541 Reactome R-MMU-6807118 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6807118.1 USP7 (HAUSP) deubiquitinates monoubiquitinated nuclear PTEN, thus promoting relocalization of PTEN to the cytosol. USP7-mediated deubiquitination of PTEN is negatively regulated by PML in the presence of DAXX, but the exact mechanism has not been elucidated (Song et al. 2008). 18716620 Pubmed 2008 The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network Song, MS Salmena, Leonardo Carracedo, Arkaitz Egia, Ainara Lo-Coco, F Teruya-Feldstein, Julie Pandolfi, Pier Paolo Nature 455:813-7 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 9904542 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9904542 Reactome DB_ID: 9879812 UniProt:Q60953 UniProt Q60953 1 EQUAL 882 EQUAL Deubiquitinated PTEN translocates to the cytosol Deubiquitinated PTEN translocates to the cytosol This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9894760 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9834442 1 2 EQUAL 403 EQUAL Reactome Database ID Release 82 9904544 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9904544 Reactome R-MMU-6807126 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6807126.1 After nuclear monoubiquitinated PTEN gets deubiquitinated by USP7 (HAUSP), it translocates to the cytosol (Song et al. 2008). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 9928118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9928118 Reactome R-MMU-8948747 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8948747.1 When monoubiquitinated by E3 ubiquitin ligases XIAP and NEDD4, PTEN translocates from the cytosol to the nucleus (Trotman et al. 2007, Van Themsche et al. 2009). USP7 (HAUSP)-mediated deubiquitination of monoubiquitinated nuclear PTEN promotes relocalization of PTEN to the cytosol (Song et al. 2008). inferred by electronic annotation IEA GO IEA Regulation of PTEN stability and activity Regulation of PTEN stability and activity This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NEDD4, WWP2, CHIP and XIAP polyubiquitinate PTEN NEDD4, WWP2, CHIP and XIAP polyubiquitinate PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9834442 1 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9816098 3 Reactome DB_ID: 9904547 1 ubiquitinylated lysine (polyubiquitin chain [cytosol]) at unknown position 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9904553 NEDD4,STUB1,WWP2 and XIAP [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity XIAP [cytosol] Nedd4 [cytosol] Stub1 [cytosol] Wwp2 [cytosol] UniProt Q60989 UniProt P46935 UniProt Q9WUD1 UniProt Q9DBH0 Reactome Database ID Release 82 9904554 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9904554 Reactome Database ID Release 82 9904556 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9904556 Reactome R-MMU-6807134 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6807134.1 Several ubiquitin ligases, including NEDD4 (Wang et al. 2007), STUB1 (CHIP) (Ahmed et al. 2012), WWP2 (Maddika et al. 2011) and XIAP (Van Themsche et al. 2009) can polyubiquitinate PTEN, targeting it for degradation. 17218260 Pubmed 2007 NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN Wang, Xinjiang Trotman, Lloyd C Koppie, Theresa Alimonti, Andrea Chen, Zhenbang Gao, Zhonghua Wang, Junru Erdjument-Bromage, H Tempst, P Cordon-Cardo, Carlos Pandolfi, Pier Paolo Jiang, Xuejun Cell 128:129-39 21532586 Pubmed 2011 WWP2 is an E3 ubiquitin ligase for PTEN Maddika, Subbareddy Kavela, Sridhar Rani, Neelam Palicharla, Vivek Reddy Pokorny, Jenny L Sarkaria, Jann N Chen, J Nat. Cell Biol. 13:728-33 22427670 Pubmed 2012 The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation Ahmed, Syed Feroj Deb, Satamita Paul, Indranil Chatterjee, Anirban Mandal, Tapashi Chatterjee, Uttara Ghosh, Mrinal K J. Biol. Chem. 287:15996-6006 inferred by electronic annotation IEA GO IEA MKRN1 polyubiquitinates PTEN MKRN1 polyubiquitinates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9834442 1 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9816098 3 Reactome DB_ID: 9904559 1 ubiquitinylated lysine (K48polyUb [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9915305 O-phospho-L-serine at 109 (in Homo sapiens) 109 EQUAL 1 EQUAL 482 EQUAL Reactome Database ID Release 82 9915308 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915308 Reactome Database ID Release 82 9915310 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915310 Reactome R-MMU-8948775 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8948775.1 The C-terminal region of the E3 ubiquitin ligase MKRN1 interacts with PTEN and polyubiquitinates it on lysine residue K289, via K48 linkage. AKT-mediated phosphorylation of MKRN1 on serine residue S109 is a pre-requisite for MKRN1 stabilization and MKRN1-mediated ubiquitination of PTEN. MKRN1 is implicated as an oncogene in cervical cancer (Lee et al. 2015). inferred by electronic annotation IEA GO IEA 2.4.2.30 TNKS and TNKS2 PARylate PTEN TNKS and TNKS2 PARylate PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9834442 1 2 EQUAL 403 EQUAL Reactome DB_ID: 29360 3 NAD(1-) [ChEBI:57540] NAD(1-) NAD(+) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD anion ChEBI 57540 Reactome DB_ID: 9915312 1 adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 40 (in Homo sapiens) 40 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 150 (in Homo sapiens) 150 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 326 (in Homo sapiens) 326 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 197277 3 nicotinamide [ChEBI:17154] nicotinamide ChEBI 17154 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9881870 TNKS1/2 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TNKS [cytosol] TNKS2 [cytosol] UniProt Q6PFX9 UniProt Q3UES3 GO 0003950 GO molecular function Reactome Database ID Release 82 9915313 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915313 Reactome Database ID Release 82 9915315 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915315 Reactome R-MMU-8948800 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8948800.1 PTEN can bind tankyrases TNKS (TNKS1) and TNKS2. The interaction involves the tankyrase binding motif at the N-terminus of PTEN (RYQEDG). TNKS and TNKS2 poly-ADP-ribosylate (PARylate) PTEN on glutamic acid residues E40 and E150 and on aspartic acid residue D326. PTEN PARylation is a pre-requisite for RNF146-mediated ubiquitination of PTEN (Li et al. 2015). 25547115 Pubmed 2015 Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth Li, N Zhang, Yajie Han, Xin Liang, Ke Wang, Jiadong Feng, Lin Wang, W Songyang, Z Lin, Chunru Yang, Liuqing Yu, Yonghao Chen, J Genes Dev. 29:157-70 inferred by electronic annotation IEA GO IEA RNF146 polyubiquitinates PARylated PTEN RNF146 polyubiquitinates PARylated PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9816098 9 Reactome DB_ID: 9915312 1 adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 40 (in Homo sapiens) 40 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 150 (in Homo sapiens) 150 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 326 (in Homo sapiens) 326 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 9908325 1 adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 40 (in Homo sapiens) 40 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 150 (in Homo sapiens) 150 EQUAL adenosine diphosphoribosyl (ADP-ribosyl) modified residue at 326 (in Homo sapiens) 326 EQUAL ubiquitinylated lysine (polyubiquitin chain [cytosol]) at 342 (in Homo sapiens) 342 EQUAL ubiquitinylated lysine (polyubiquitin chain [cytosol]) at 344 (in Homo sapiens) 344 EQUAL ubiquitinylated lysine (polyubiquitin chain [cytosol]) at 349 (in Homo sapiens) 349 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9881850 UniProt:Q9CZW6 UniProt Q9CZW6 1 EQUAL 359 EQUAL Reactome Database ID Release 82 9915316 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915316 Reactome Database ID Release 82 9915318 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9915318 Reactome R-MMU-8948832 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8948832.1 The E3 ubiquitin ligase RNF146 possesses a PAR recognition domain (WWE) which binds to PARylated PTEN. RNF146 polyubiquitinates PARylated PTEN, with lysine residues K342, K344 and K349 as major ubiquitination sites. RNF146-mediated ubiquitination targets PTEN for proteasome-mediated degradation (Li et al. 2015). inferred by electronic annotation IEA GO IEA Proteasome degrades polyubiquitinated PTEN Proteasome degrades polyubiquitinated PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9908327 1 PolyUb-PTEN, K48polyUb-K289-PTEN, PolyUb-K324,K344,K349-RibC-E40,E150,D326-PTEN [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Pten [cytosol] phospho-Pten [cytosol] Converted from EntitySet in Reactome Reactome DB_ID: 9816098 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9816168 26S proteasome [cytosol] 26S proteasome Reactome DB_ID: 1236812 1 UniProt:P99026 Psmb4 Psmb4 Lmp3 Psmb4 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:16857966, PubMed:22341445). Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome (By similarity). Interacts with PRPF19 (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor tissues (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt P99026 46 EQUAL 264 EQUAL Reactome DB_ID: 9816104 1 UniProt:O09061 Psmb1 Psmb1 Psmb1 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:16857966, PubMed:22341445). Interacts with SERPINB2 (By similarity). Interacts with RFPL4A (PubMed:12525704).TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt O09061 29 EQUAL 241 EQUAL Reactome DB_ID: 1236823 1 UniProt:Q9QUM9 Psma6 Psma6 Psma6 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:16857966, PubMed:22341445). Interacts with ALKBH4 (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor tissues (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt Q9QUM9 1 EQUAL 246 EQUAL Reactome DB_ID: 9816110 1 UniProt:P62192 UniProt P62192 2 EQUAL 440 EQUAL Reactome DB_ID: 9816120 1 UniProt:P62334 UniProt P62334 1 EQUAL 389 EQUAL Reactome DB_ID: 1236853 1 UniProt:P28076 Psmb9 Psmb9 Lmp2 Ring12 Psmb9 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Contributes to NFKBIA degradation and subsequently NFKB1 generation.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB6. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Interacts with NCOA1, NCOA2 and NCOA3.TISSUE SPECIFICITY Detected in liver (at protein level). Expressed at high levels in the thymus, spleen, lung, heart and liver. Expressed at moderate levels in the kidney.INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Up-regulated by heat shock treatment. Down-regulated by EGR1 in neuronal cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.DISRUPTION PHENOTYPE Depletion of LMP2 by RNAi suppresses expression and activities of the matrix metalloproteinase MMP2 and MMP9 by blocking the transfer of active NF-kappa-B heterodimers into the nucleus.SIMILARITY Belongs to the peptidase T1B family. UniProt P28076 21 EQUAL 219 EQUAL Reactome DB_ID: 9816146 1 UniProt:Q9CR00 Psmd9 UniProt Q9CR00 1 EQUAL 223 EQUAL Reactome DB_ID: 1236811 1 UniProt:O35955 Psmb10 Psmb10 Psmb10 Lmp10 Mecl1 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Plays a role in determining the T-cell repertoire for an antiviral T-cell response.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB7. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.DISRUPTION PHENOTYPE Impaired response of cytotoxic T-lymphocyte (CTL) to dominant epitopes of lymphocytic choriomeningitis virus (LCMV).SIMILARITY Belongs to the peptidase T1B family. UniProt O35955 40 EQUAL 273 EQUAL Reactome DB_ID: 1236868 1 UniProt:O70435 Psma3 Psma3 Psma3 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:16857966, PubMed:22341445). Interacts with AURKB. Interacts with CDKN1A. Interacts with MDM2 and RB1. Interacts with the C-terminus of TBXA2R isoform 2. Interacts with DNAJB2.TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt O70435 2 EQUAL 255 EQUAL Reactome DB_ID: 9816106 1 UniProt:O55234 Psmb5 Psmb5 Psmb5 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB5 displays a chymotrypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:16857966, PubMed:22341445). Directly interacts with POMP (By similarity). Interacts with ABCB1 and TAP1 (By similarity).TISSUE SPECIFICITY Expressed in uterus at the embryo implantation site.INDUCTION Up-regulated in embryonic fibroblasts and neuroblastoma cells by antioxidants through the Nrf2-ARE pathway (at protein level). Up-regulated by the antioxidant dithiolethione (D3T) in liver, small intestine and brain (at protein level). Down-regulated under lithium treatment.SIMILARITY Belongs to the peptidase T1B family. UniProt O55234 60 EQUAL 263 EQUAL Reactome DB_ID: 1236775 1 UniProt:P70195 Psmb7 Psmb7 Psmb7 Mmc14 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB7 displays a trypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.INDUCTION Up-regulated by the antioxidant dithiolethione (D3T) in colon (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt P70195 44 EQUAL 277 EQUAL Reactome DB_ID: 9816142 1 UniProt:P26516 Psmd7 UniProt P26516 1 EQUAL 324 EQUAL Reactome DB_ID: 9816166 1 Ghost homologue of SEM1 [cytosol] Ghost homologue of SEM1 Reactome DB_ID: 9816152 1 UniProt:P61290 Psme3 UniProt P61290 2 EQUAL 254 EQUAL Reactome DB_ID: 9816148 1 UniProt:P97371 Psme1 UniProt P97371 1 EQUAL 249 EQUAL Reactome DB_ID: 9816164 1 UniProt:Q8BG41 Psmb11 Psmb11 Psmb11 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Incorporated instead of PSMB5 or PSMB8, this unit reduces the chymotrypsin-like activity of the proteasome. Plays a pivotal role in development of CD8-positive T-cells.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Incorporated instead of PSMB5 and PSMB8.TISSUE SPECIFICITY Expressed exclusively in cortical thymic epithelial cells.DISRUPTION PHENOTYPE Displays defective development of CD8-positive T-cells in the thymus.SIMILARITY Belongs to the peptidase T1B family. UniProt Q8BG41 50 EQUAL 300 EQUAL Reactome DB_ID: 1236877 1 UniProt:Q9Z2U1 Psma5 Psma5 Psma5 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:16857966, PubMed:22341445). PSMA5 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt Q9Z2U1 1 EQUAL 241 EQUAL Reactome DB_ID: 9816126 1 UniProt:Q8BG32 Psmd11 UniProt Q8BG32 2 EQUAL 422 EQUAL Reactome DB_ID: 9816136 1 UniProt:O35226 Psmd4 UniProt O35226 1 EQUAL 377 EQUAL Reactome DB_ID: 9816154 1 UniProt:Q8BHL8 Psmf1 UniProt Q8BHL8 1 EQUAL 271 EQUAL Reactome DB_ID: 9816118 1 UniProt:P62196 UniProt P62196 2 EQUAL 406 EQUAL Reactome DB_ID: 9816128 1 UniProt:Q9D8W5 Psmd12 UniProt Q9D8W5 2 EQUAL 456 EQUAL Reactome DB_ID: 9816114 1 UniProt:O88685 UniProt O88685 1 EQUAL 439 EQUAL Reactome DB_ID: 9816130 1 UniProt:Q9WVJ2 Psmd13 UniProt Q9WVJ2 1 EQUAL 376 EQUAL Reactome DB_ID: 9816124 1 UniProt:Q9Z2X2 Psmd10 UniProt Q9Z2X2 1 EQUAL 226 EQUAL Reactome DB_ID: 1236864 1 UniProt:P28063 Psmb8 Psmb8 Lmp7 Mc13 Psmb8 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. May participate in the inflammatory response pathway. Required for adipocyte differentiation (PubMed:21881205, PubMed:22341445, PubMed:8066463). May be involved in the generation of spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (By similarity).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB5. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Directly interacts with POMP. Interacts with TAP1.TISSUE SPECIFICITY Detected in liver (at protein level). Expressed in spleen, thymus, lung, liver, heart and, at a very low level, in kidney. Not expressed in brain nor testis.INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Down-regulated in spleen by deoxynivalenol (DON), a mycotoxin that alters immune functions. Down-regulated by the selective inhibitor PR-957. Up-regulated by heat shock treatment. Down-regulated by EGR1 in neuronal cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.POLYMORPHISM The allele, LMP7k/LMP7s/LMPf/LMP7r/LMPcas4/LMPg7 found in strains NMRI, B10.BR, SJL, A.CA, B10.RIII, B10.cas4 and NOD may be post-translationally modified. Allele LMP7q is found in strain DBA/1J.SIMILARITY Belongs to the peptidase T1B family. UniProt P28063 73 EQUAL 276 EQUAL Reactome DB_ID: 9816132 1 UniProt:Q8VDM4 Psmd2 UniProt Q8VDM4 1 EQUAL 908 EQUAL Reactome DB_ID: 1236802 1 UniProt:Q9R1P4 Psma1 Psma1 Psma1 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:16857966). Interacts with NOTCH3 (By similarity). Interacts with ZFAND1 (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor tissues. Up-regulated by the antioxidant dithiolethione (D3T) in liver, lung and colon (at the protein level).PTM C-terminal extension is partially cleaved off by limited proteolysis leading to a conversion of the proteasome from its latent into its active form.SIMILARITY Belongs to the peptidase T1A family. UniProt Q9R1P4 1 EQUAL 263 EQUAL Reactome DB_ID: 9816140 1 UniProt:Q99JI4 Psmd6 UniProt Q99JI4 1 EQUAL 389 EQUAL Reactome DB_ID: 9816144 1 UniProt:Q9CX56 Psmd8 UniProt Q9CX56 1 EQUAL 350 EQUAL Reactome DB_ID: 9816161 1 UniProt:Q9CWH6 Psma8 Psma8 Psma7l Psma8 FUNCTION Component of the spermatoproteasome, a proteasome specifically found in testis that promotes acetylation-dependent degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis (PubMed:23706739, PubMed:31358751, PubMed:31437213). The proteasome is a protein complex that degrades unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds (Probable). Required for 20S core proteasome assembly, essential for the degradation of meiotic proteins RAD51 and RPA1 at late prophase I and the progression of meiosis I during spermatogenesis (PubMed:31358751). Localizes to the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I (PubMed:31437213).SUBUNIT Component of the outer alpha-ring of the 20S proteasome core which is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure (PubMed:23706739, PubMed:31358751). The catalytic chamber with the active sites is on the inside of the barrel (Probable). Interacts with canonical subunits of the spermatoproteasome, including proteasome activators PSME4 (also called PA200) and PSME3 (also called PA28-gamma) (PubMed:31437213). Interacts with proteasome-interacting proteins chaperones including CCT6B and CCT2, ubiquitin ligases (TRIP12, NEDD4, TRIM36 and RAD18), and ubiquitin specific proteases such as USP9X, USP34, USP5 and USP47 (PubMed:31437213). Interacts with meiotic proteins cyclin dependent kinase CDK1 and the ATPase TRIP13 as well as proteins of the synaptonemal complex SIX6OS1 and SYCE3 (PubMed:31437213).DEVELOPMENTAL STAGE In testes, expressed in spermatocytes at the pachytene stage (weakly in early pachynema and strongly in late pachynema), and its expression persisted thereafter throughout spermatogenesis.DISRUPTION PHENOTYPE Knockout mice were obtained according to the expected Mendelian ratios and showed no obvious phenotypes with respect to viability and development; however males show infertility (PubMed:31358751, PubMed:31437213). PSMA8-null spermatocytes exhibit delayed M-phase entry and are finally arrested at this stage, resulting in male infertility (PubMed:31358751, PubMed:31437213).SIMILARITY Belongs to the peptidase T1A family.CAUTION Predicted to have endopeptidase activity (By similarity). However, as it is located in the outer alpha-ring, it is suggested to lack catalytic activity and preferentially interact with regulatory complexes such as PSME4/PA200. UniProt Q9CWH6 1 EQUAL 256 EQUAL Reactome DB_ID: 1236839 1 UniProt:Q9R1P0 Psma4 Psma4 Psma4 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:16857966, PubMed:22341445).TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1A family. UniProt Q9R1P0 1 EQUAL 261 EQUAL Reactome DB_ID: 9816116 1 UniProt:P54775 UniProt P54775 1 EQUAL 418 EQUAL Reactome DB_ID: 9816112 1 UniProt:P46471 UniProt P46471 2 EQUAL 433 EQUAL Reactome DB_ID: 9816100 1 UniProt:O35593 UniProt O35593 1 EQUAL 310 EQUAL Reactome DB_ID: 9816102 1 UniProt:Q9Z2U0 Psma7 Psma7 Psma7 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:16857966, PubMed:22341445). PSMA7 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (By similarity). Interacts with HIF1A (By similarity). Interacts with RAB7A (By similarity). Interacts with PRKN (By similarity). Interacts with ABL1 and ABL2 (By similarity). Interacts with EMAP2 (By similarity). Interacts with MAVS (By similarity).TISSUE SPECIFICITY Detected in liver (at protein level).INDUCTION Up-regulated in liver tumor tissues.PTM Phosphorylation by ABL1 or ABL2 leads to an inhibition of proteasomal activity and cell cycle transition blocks.SIMILARITY Belongs to the peptidase T1A family. UniProt Q9Z2U0 1 EQUAL 248 EQUAL Reactome DB_ID: 1236795 1 UniProt:Q9R1P1 Psmb3 Psmb3 Psmb3 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt Q9R1P1 2 EQUAL 205 EQUAL Reactome DB_ID: 9816158 1 UniProt:Q5SSW2 Psme4 UniProt Q5SSW2 1 EQUAL 1843 EQUAL Reactome DB_ID: 9816138 1 UniProt:Q8BJY1 Psmd5 UniProt Q8BJY1 2 EQUAL 504 EQUAL Reactome DB_ID: 1236800 1 UniProt:P49722 Psma2 Psma2 Psma2 Lmpc3 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.TISSUE SPECIFICITY Detected in liver (at protein level).PTM Phosphorylated on tyrosine residues; which may be important for nuclear import.SIMILARITY Belongs to the peptidase T1A family. UniProt P49722 2 EQUAL 234 EQUAL Reactome DB_ID: 9816122 1 UniProt:Q3TXS7 Psmd1 UniProt Q3TXS7 1 EQUAL 953 EQUAL Reactome DB_ID: 9816134 1 UniProt:P14685 Psmd3 UniProt P14685 1 EQUAL 534 EQUAL Reactome DB_ID: 9816150 1 UniProt:P97372 Psme2 UniProt P97372 2 EQUAL 239 EQUAL Reactome DB_ID: 1236756 1 UniProt:Q9R1P3 Psmb2 Psmb2 Psmb2 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.TISSUE SPECIFICITY Detected in liver (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt Q9R1P3 1 EQUAL 201 EQUAL Reactome DB_ID: 9816108 1 UniProt:Q60692 Psmb6 Psmb6 Psmb6 Lmp19 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB6 displays a peptidylglutamyl-hydrolyzing activity also termed postacidic or caspase-like activity, meaning that the peptides bond hydrolysis occurs directly after acidic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.INDUCTION Up-regulated by the antioxidant dithiolethione (D3T) in liver, lung and small intestine (at protein level).SIMILARITY Belongs to the peptidase T1B family. UniProt Q60692 35 EQUAL 239 EQUAL Reactome Database ID Release 82 9816168 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9816168 Reactome R-MMU-68819 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-68819.1 GO 0004175 GO molecular function Reactome Database ID Release 82 9816169 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9816169 Reactome Database ID Release 82 9908329 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9908329 Reactome R-MMU-8850992 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8850992.1 PTEN, polyubiquitinated by either NEDD4 (Wang et al. 2007), STUB1 (CHIP) (Ahmed et al. 2011), WWP2 (Maddika et al. 2011), XIAP (Van Themsche et al. 2009), MKRN1 (Lee et al. 2015) or RNF146 (Li et al. 2015), is degraded by the proteasome. inferred by electronic annotation IEA GO IEA 3.4.19.12 USP13 and OTUD3 deubiquitinate PTEN USP13 and OTUD3 deubiquitinate PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9904559 1 ubiquitinylated lysine (K48polyUb [cytosol]) at 289 (in Homo sapiens) 289 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 29356 1 Reactome DB_ID: 9834442 1 2 EQUAL 403 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9816098 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9904565 USP13,OTUD3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Otud3 [cytosol] USP13 [cytosol] UniProt B1AZ99 UniProt Q5BKP2 Reactome Database ID Release 82 9904566 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9904566 Reactome Database ID Release 82 9904568 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9904568 Reactome R-MMU-6807206 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6807206.1 Several ubiquitin proteases deubiquitinate polyubiquitinated PTEN. USP13 and OTUD3 prolong the half-life of PTEN by preventing its proteasome-mediated degradation. Loss of USP13 or OTUD3 expression promotes AKT activation and cancer aggressiveness (Zhang et al. 2013, Yuan et al. 2015). 24270891 Pubmed 2013 Deubiquitylation and stabilization of PTEN by USP13 Zhang, Jinsong Zhang, Peijing Wei, Yongkun Piao, Hai-Long Wang, W Maddika, Subbareddy Wang, Min Chen, Dahu Sun, Yutong Hung, Mien-Chie Chen, J Ma, Li Nat. Cell Biol. 15:1486-94 26280536 Pubmed 2015 Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis Yuan, Lin Lv, Yanrong Li, Hongchang Gao, Haidong Song, Shanshan Zhang, Yuan Xing, Guichun Kong, Xiangzhen Wang, Lijing Li, Yang Zhou, Tao Gao, Daming Xiao, Zhi-Xiong Yin, Yuxin Wei, Wenyi He, Fuchu Zhang, Lingqiang Nat. Cell Biol. 17:1169-81 inferred by electronic annotation IEA GO IEA PTEN binds FRK PTEN binds FRK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9907498 1 UniProt:Q922K9 UniProt Q922K9 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL O4'-phospho-L-tyrosine [MOD:00048] 1 EQUAL 505 EQUAL Reactome DB_ID: 9834442 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9907500 1 PTEN:p-Y387-FRK [cytosol] PTEN:p-Y387-FRK Reactome DB_ID: 9907498 1 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL 1 EQUAL 505 EQUAL Reactome DB_ID: 9834442 1 2 EQUAL 403 EQUAL Reactome Database ID Release 82 9907500 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9907500 Reactome R-MMU-8847960 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8847960.1 Reactome Database ID Release 82 9907502 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9907502 Reactome R-MMU-8847968 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8847968.1 FRK (RAK), a SRC family member kinase, binds PTEN. The interaction involves the SH3 domain of FRK and the C2 domain of PTEN (Yim et al. 2009). Like other SRC family members, FRK is autophosphorylated on a C-terminal tyrosine residue Y387. FRK possesses a nuclear localization signal and is found in both nucleus and the cytosol (Cance et al. 1994). 19345329 Pubmed 2009 Rak functions as a tumor suppressor by regulating PTEN protein stability and function Yim, Eun-Kyoung Peng, Guang Dai, Hui Hu, Ruozhen Li, Kaiyi Lu, Yiling Mills, Gordon B Meric-Bernstam, Funda Hennessy, Bryan T Craven, Rolf J Lin, Shiaw-Yih Cancer Cell 15:304-14 7696183 Pubmed 1994 Rak, a novel nuclear tyrosine kinase expressed in epithelial cells Cance, W G Craven, R J Bergman, M Xu, L Alitalo, K Liu, E T Cell Growth Differ. 5:1347-55 inferred by electronic annotation IEA GO IEA 2.7.10.2 FRK phosphorylates PTEN FRK phosphorylates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 9907500 1 Reactome DB_ID: 9907505 1 O4'-phospho-L-tyrosine at 336 (in Homo sapiens) 336 EQUAL 2 EQUAL 403 EQUAL Reactome DB_ID: 9907498 1 O4'-phospho-L-tyrosine at 387 (in Homo sapiens) 387 EQUAL 1 EQUAL 505 EQUAL Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9907500 Reactome Database ID Release 82 9907506 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9907506 Reactome Database ID Release 82 9907508 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9907508 Reactome R-MMU-8847977 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8847977.1 FRK tyrosine kinase (RAK) phosphorylates PTEN on tyrosine residue Y336. FRK-mediated phosphorylation inhibits NEDD4-mediated polyubiquitination and subsequent degradation of PTEN, thus increasing PTEN half-life. FRK-mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). inferred by electronic annotation IEA GO IEA 2.7.11.1 Casein kinase II phosphorylates PTEN Casein kinase II phosphorylates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 5 Reactome DB_ID: 9834442 1 2 EQUAL 403 EQUAL Reactome DB_ID: 29370 5 Reactome DB_ID: 9908305 1 O-phospho-L-serine at 370 (in Homo sapiens) 370 EQUAL O-phospho-L-serine at 380 (in Homo sapiens) 380 EQUAL O-phospho-L-threonine at 382 (in Homo sapiens) 382 EQUAL O-phospho-L-threonine at 383 (in Homo sapiens) 383 EQUAL O-phospho-L-serine at 385 (in Homo sapiens) 385 EQUAL 2 EQUAL 403 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9835377 Casein kinase II [cytosol] Casein kinase II Reactome DB_ID: 9835361 2 UniProt:P67871 Csnk2b Csnk2b Csnk2b Ck2n FUNCTION Regulatory subunit of casein kinase II/CK2. As part of the kinase complex regulates the basal catalytic activity of the alpha subunit a constitutively active serine/threonine-protein kinase that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine (PubMed:16818610). Participates in Wnt signaling (PubMed:10806215).SUBUNIT Casein kinase II/CK2 is a tetramer composed of an alpha subunit, an alpha' subunit and two beta subunits. The beta subunit dimerization is mediated by zinc ions. Interacts with CD163. Also component of a CK2-SPT16-SSRP1 complex composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B, the complex associating following UV irradiation (By similarity). Interacts with DYNLT2. Interacts with MUSK; mediates phosphorylation of MUSK by CK2. Interacts with FGF1; this interaction is increased in the presence of FIBP, suggesting a possible cooperative interaction between CSNKB and FIBP in binding to FGF1 (By similarity).PTM Phosphorylated by alpha subunit.SIMILARITY Belongs to the casein kinase 2 subunit beta family. UniProt P67871 2 EQUAL 215 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9835375 2 CSNK2(A1:A1/A1:A2/A2:A2) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 9835377 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9835377 Reactome R-MMU-201711 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-201711.1 Reactome Database ID Release 82 9835378 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9835378 Reactome Database ID Release 82 9908307 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9908307 Reactome R-MMU-8850945 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8850945.1 Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. S370 and S385 are the main CK2 phosphorylation sites in PTEN (Torres and Pulido 2001, Miller et al. 2002). CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002). 11035045 Pubmed 2001 The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation Torres, J Pulido, R J. Biol. Chem. 276:993-8 12297295 Pubmed 2002 Direct identification of PTEN phosphorylation sites Miller, Susan J Lou, David Y Seldin, David C Lane, William S Neel, Benjamin G FEBS Lett. 528:145-53 inferred by electronic annotation IEA GO IEA PREX2 binds PTEN and inhibits it PREX2 binds PTEN and inhibits it This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9908313 1 PTEN, p-3S,2T-PTEN [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Pten [cytosol] phospho-Pten [cytosol] Reactome DB_ID: 9908311 1 UniProt:Q3LAC4 Prex2 UniProt Q3LAC4 1 EQUAL 1606 EQUAL Reactome DB_ID: 9908315 1 PREX2:PTEN,p-3S,2T-PTEN [cytosol] PREX2:PTEN,p-3S,2T-PTEN Converted from EntitySet in Reactome Reactome DB_ID: 9908313 1 Reactome DB_ID: 9908311 1 1 EQUAL 1606 EQUAL Reactome Database ID Release 82 9908315 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9908315 Reactome R-MMU-8850934 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8850934.1 Reactome Database ID Release 82 9908317 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9908317 Reactome R-MMU-8850961 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8850961.1 PREX2, a RAC1 guanine nucleotide exchange factor (GEF), binds to PTEN and inhibits its catalytic activity, resulting in enhanced PI3K/AKT signaling (Fine et al. 2009). The interaction involves the inositol polyphosphate 4-phosphatase domain and the pleckstrin homology (PH) domain of PREX2 and the PDZ binding domain, the phosphatase domain and the C2 domain of PTEN (Fine et al. 2009, Hodakoski et al. 2014). PREX2 binds both the unphosphorylated PTEN and PTEN phosphorylated at the C-terminal tail by casein kinase II, but inhibits the lipid phosphatase activity of phosphorylated PTEN only (Hodakoski et al. 2014). The GEF activity of PREX2 is not needed for PTEN inhibition (Fine et al. 2009).<p>PREX2 is frequently overexpressed in breast and prostate cancer (Fine et al. 2009) and mutated in melanoma (Berger et al. 2012). 19729658 Pubmed 2009 Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a Fine, Barry Hodakoski, Cindy Koujak, Susan Su, Tao Saal, Lao H Maurer, Matthew Hopkins, Benjamin Keniry, Megan Sulis, ML Mense, Sarah Hibshoosh, Hanina Parsons, R Science 325:1261-5 22622578 Pubmed 2012 Melanoma genome sequencing reveals frequent PREX2 mutations Berger, Michael F Hodis, Eran Heffernan, Timothy P Deribe, Yonathan Lissanu Lawrence, Michael S Protopopov, Alexei Ivanova, Elena Watson, Ian R Nickerson, Elizabeth Ghosh, Papia Zhang, Hailei Zeid, Rhamy Ren, Xiaojia Cibulskis, K Sivachenko, Andrey Y Wagle, Nikhil Sucker, Antje Sougnez, Carrie Onofrio, R Ambrogio, Lauren Auclair, Daniel Fennell, Timothy Carter, Scott L Drier, Yotam Stojanov, Petar Singer, Meredith A Voet, Douglas Jing, Rui Saksena, Gordon Barretina, Jordi Ramos, AH Pugh, Trevor J Stransky, N Parkin, Melissa Winckler, W Mahan, Scott Ardlie, Kristin Baldwin, Jennifer Wargo, Jennifer Schadendorf, Dirk Meyerson, M Gabriel, Stacey B Golub, Todd R Wagner, Stephan N Lander, Eric S Getz, G Chin, Lynda Garraway, Levi A Nature 485:502-6 24367090 Pubmed 2014 Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis Hodakoski, Cindy Hopkins, Benjamin D Barrows, Douglas Mense, Sarah M Keniry, Megan Anderson, Karen E Kern, Philip A Hawkins, Phillip T Stephens, Len R Parsons, R Proc. Natl. Acad. Sci. U.S.A. 111:155-60 inferred by electronic annotation IEA GO IEA TRIM27 binds PTEN TRIM27 binds PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9834442 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9908331 1 UniProt:Q62158 UniProt Q62158 1 EQUAL 513 EQUAL Reactome DB_ID: 9908333 1 PTEN:TRIM27 [cytosol] PTEN:TRIM27 Reactome DB_ID: 9834442 1 2 EQUAL 403 EQUAL Reactome DB_ID: 9908331 1 1 EQUAL 513 EQUAL Reactome Database ID Release 82 9908333