BioPAX pathway converted from "PI3K/AKT Signaling in Cancer" in the Reactome database. PI3K/AKT Signaling in Cancer PI3K/AKT Signaling in Cancer Class IA PI3K is a heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). In the absence of activating signals, the regulatory subunit stabilizes the catalytic subunit while inhibiting its activity. The complex becomes activated when extracellular signals stimulate the phosphorylation of the cytoplasmic domains of transmembrane receptors or receptor-associated proteins. The p85 regulatory subunit binds phosphorylated motifs of activator proteins, which induces a conformational change that relieves p85-mediated inhibition of the p110 catalytic subunit and enables PI3K to phosphorylate PIP2 to form PIP3. The phosphoinositide kinase activity of PI3K is opposed by the phosphoinositide phosphatase activity of PTEN. <br><br>PIP3 acts as a messenger that recruits PDPK1 (PDK1) and AKT (AKT1, AKT2 or AKT3) to the plasma membrane. PDPK1 also possesses a low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane. Binding of AKT to PIP3 induces a conformational change that enables TORC2 complex to phosphorylate AKT at a conserved serine residue (S473 in AKT1). Phosphorylation at the serine residue enables AKT to bind to PDPK1 and exposes a conserved threonine residue (T308) that is phosphorylated by PDPK1. AKT phosphorylated at both serine and threonine residues dissociates from the plasma membrane and acts as a serine/threonine kinase that phosphorylates a number of cytosolic and nuclear targets involved in regulation of cell metabolism, survival and gene expression. For a recent review, please refer to Manning and Cantley, 2007. <br> Signaling by PI3K/AKT is frequently constitutively activated in cancer. This activation can be via gain-of-function mutations in PI3KCA (encoding catalytic subunit p110alpha), PIK3R1 (encoding regulatory subunit p85alpha) and AKT1. The PI3K/AKT pathway can also be constitutively activated by loss-of-function mutations in tumor suppressor genes such as PTEN. <br> Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011). While AKT1 gene copy number, expression level and phosphorylation are often increased in cancer, only one low frequency point mutation has been repeatedly reported in cancer and functionally studied. This mutation represents a substitution of a glutamic acid residue with lysine at position 17 of AKT1, and acts by enabling AKT1 to bind PIP2. PIP2-bound AKT1 is phosphorylated by TORC2 complex and by PDPK1 that is always present at the plasma membrane, due to low affinity for PIP2. Therefore, E17K substitution abrogates the need for PI3K in AKT1 activation (Carpten et al. 2007, Landgraf et al. 2008). <br> Loss-of-function mutations affecting the phosphatase domain of PTEN are frequently found in sporadic cancers (Kong et al. 1997, Lee et al. 1999, Han et al. 2000), as well as in PTEN hamartoma tumor syndromes (PHTS) (Marsh et al. 1998). PTEN can also be inactivated by gene deletion or epigenetic silencing, or indirectly by overexpression of microRNAs that target PTEN mRNA (Huse et al. 2009). Cells with deficient PTEN function have increased levels of PIP3, and therefore increased AKT activity. For a recent review, please refer to Hollander et al. 2011.<br> Because of their clear involvement in human cancers, PI3K and AKT are targets of considerable interest in the development of small molecule inhibitors. Although none of the currently available inhibitors display preference for mutant variants of PIK3CA or AKT, several inhibitors targeting the wild-type kinases are undergoing clinical trials. These include dual PI3K/mTOR inhibitors, class I PI3K inhibitors, pan-PI3K inhibitors, and pan-AKT inhibitors. While none have yet been approved for clinical use, these agents show promise for future therapeutics. In addition, isoform-specific PI3K and AKT inhibitors are currently being developed, and may provide more specific treatments along with reduced side-effects. For a recent review, please refer to Liu et al. 2009. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Constitutive Signaling by Aberrant PI3K in Cancer Constitutive Signaling by Aberrant PI3K in Cancer Signaling by PI3K/AKT is frequently constitutively activated in cancer via gain-of-function mutations in one of the two PI3K subunits - PI3KCA (encoding the catalytic subunit p110alpha) or PIK3R1 (encoding the regulatory subunit p85alpha). Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011). Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 2.7.1.153 PI3K gain of function mutants phosphorylate PIP2 to PIP3 PI3K gain of function mutants phosphorylate PIP2 to PIP3 Constitutively active PI3K complex produces PIP3 in the absence of growth stimuli, resulting in aberrant activation of downstream AKT signaling that positively regulates cell growth and survival. The PIK3CA gene, encoding the catalytic subunit of PI3K (p110alpha), is one of the most frequently mutated oncogenes in cancer. Hotspot mutations are found in the helical domain and kinase domain of PIK3CA, with the most frequent mutations being E545K substitution in the helical domain and H1047R substitution in the kinase domain.<br> The oncogenic PIK3CA mutants annotated here preserve their ability to bind PIK3R1 (p85alpha) regulatory subunit, but are constitutively active either because the inhibitory interactions with PIK3R1 are relieved, or because the conformation of the catalytic domain is changed. Missense mutations that result in substitution of amino acids at positions 542, 545 or 546 of PI3K disrupt an inhibitory interaction between the helical domain of PIK3CA and the nSH2 domain of PIK3R1. The effect of substitution of glutamic acid residue at position 545 has been studied in detail in PIK3CA E545K mutant, where glutamic acid is replaced with lysine (Miled et al. 2007, Huang et al. 2007, Zhao et al. 2005). The gain-of-function has been experimentally confirmed for PIK3CA E545A mutant (Horn et al. 2008), while PIK3CA E545G, PIK3CA E545Q and PIK3CA E545V mutants are assumed to behave similarly. The structural and functional consequences of glutamic acid to lysine substitution at position 542, in PIK3CA E542K mutant, have been established (Miled et al. 2007, Horn et al. 2008) and are extrapolated to PIK3CA E542Q and PIK3CA E542V mutants. A less frequent substitution of glutamine residue at position 546 follows the same mechanism, as shown for PIK3CA Q546K mutant (Miled et al. 2007) and extrapolated to PIK3CA Q546E, PIK3CA Q546H, PIK3CA Q546L, PIK3CA Q546P and PIK3CA Q546R mutants.<br> In the kinase domain of PIK3CA, substitution of histidine residue at position 1047 or methionine residue at position 1043, detected in PIK3CA H1047R, PIK3CA H1047L, PIK3CA H1047Y, PIK3CA M1043I, PIK3CA M1043T and PIK3CA M1043V mutants, is predicted to change the conformation of the activation loop (Huang et al. 2007) and was shown to confer constitutive activity, in the absence of growth factors, to PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants (Zhao et al. 2005, Horn et al. 2008). The catalytic activity of PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants may be further increased by binding of PIK3R1 regulatory subunit to phosphopeptides generated by activated receptor tyrosine kinases (Hon et al. 2011). PIK3CA H1047Y, PIK3CA M1043T and PIK3CA M1043V mutants are expected to behave similarly.<br> The arginine residue at position 38 of PIK3CA (R38) is located at a contact site between the ABD and kinase domains of PIK3CA. Substitution of this arginine residue with histidine in PIK3CA R38H mutant is likely to disrupt the interaction between the ABD domain and the kinase domain, causing a conformational change of the kinase domain that leads to increased enzymatic activity (Huang et al. 2007). PIK3CA R38H mutant shows reduced PIK3R1 binding and modestly increased catalytic activity (measured indirectly, via AKT1 phosphorylation) under serum starved conditions (Zhao et al. 2005). PIK3CA R38C, PIK3CA R38G and PIK3CA R38S mutants are expected to behave similarly.<br> Mutations in other conserved domains of PIK3CA, such as membrane-binding C2 domain (Mandelker et al. 2009), have not been annotated as their mechanism of action needs to be further elucidated.<br> Although less common than mutations in PIK3CA, mutations in PIK3R1, encoding the regulatory subunit of PI3K (p85alpha) have been recently described. Mutations mapping to iSH2 and nSH2 domains, the two domains of PIK3R1 involved in the inhibition of PIK3CA, which were shown to result in constitutive activity of PIK3R1 complex, are annotated here. An experimentally studied nSH2 domain mutant is PIK3R1 G376R (Sun et al. 2010). PIK3R1 iSH2 domain mutants, affected by amino acid substitutions and small inframe deletions, PIK3R1 D560Y (Jaiswal et al. 2009), PIK3R1 N564D (Jaiswal et al. 2009), PIK3R1 N564K (Sun et al. 2010), PIK3R1 H450_E451del (Urick et al. 2011), PIK3R1 K459del (Urick et al. 2011), PIK3R1 R574_T576del (Urick et al. 2011) and PIK3R1 Y463_L466del (Urick et al. 2011), were all shown to bind PIK3CA and confer constitutive activity to PI3K complex. PIK3R1 D560H, PIK3R1 R574I and PIK3R1 R574T mutants are expected to behave similarly to functionally characterized D560 and R574 substitution mutants.<br> Co-occurrence of PIK3CA and PIK3R1 mutations has been documented in some tumors, but since it is rare and the exact clinical combinations of PIK3CA and PIK3R1 mutants have not been studied, complexes of PIK3CA mutants with PIK3R1 mutants are not shown (Urick et al. 2011).<br> Although rare, perturbations in genes encoding other isoforms of PI3K subunits have also been reported in cancers. Mutations in PIK3R2, encoding PI3K regulatory subunit isoform p85beta, are found infrequently in endometrial cancers, but have not been functionally studied (Cheung et al. 2011). They are not shown in this context. PIK3CB, encoding PI3K catalytic subunit isoform p110beta, can be overexpressed in cancer, mainly due to genomic gain. Several studies have shown that PTEN deficient cancer cell lines depend on PIK3CB (p110beta) for AKT activation and sustained growth (Wee et al. 2008, Jiang et al. 2010, Chen et al. 2011). PIK3CB activation synergizes with PTEN loss in mouse prostate cancer model (Jia et al. 2008). Mutations in PIK3CB are very rare, have not been functionally studied, and are therefore not shown. Structural studies indicate that, in comparison with PIK3CA (p110alpha), PIK3CB (p110beta) and PIK3CD (p110delta) form additional inhibitory contacts with the regulatory subunit p85alpha, and are therefore probably less prone to mutational activation (Burke et al. 2011). <br> For more information, please refer to recent reviews by Liu et al. 2009 and Vogt et al. 2009. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 179856 1 plasma membrane GO 0005886 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) Reactome http://www.reactome.org ChEBI 58456 Reactome DB_ID: 113592 1 cytosol GO 0005829 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 179838 1 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) [ChEBI:57836] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) 2,3-bis(alkanoyloxy)propyl (1S,2S,3R,4S,5S,6S)-2,6-dihydroxy-3,4,5-tris(phosphonatooxy)cyclohexyl phosphate ChEBI 57836 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2394006 PI3K mutants [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 2394010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2394010 Reactome Database ID Release 82 2394007 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2394007 Reactome R-HSA-2394007 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2394007.1 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 19962665 Pubmed 2009 Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation Jaiswal, Bijay S Janakiraman, Vasantharajan Kljavin, Noelyn M Chaudhuri, Subhra Stern, Howard M Wang, Weiru Kan, Zhengyan Dbouk, Hashem A Peters, Brock A Waring, Paul Dela Vega, Trisha Kenski, Denise M Bowman, Krista K Lorenzo, Maria Li, Hong Wu, Jiansheng Modrusan, Zora Stinson, Jeremy Eby, Michael Yue, Peng Kaminker, Josh S de Sauvage, Frederic J Backer, Jonathan M Seshagiri, Somasekar Cancer Cell 16:463-74 21188471 Pubmed 2011 PTEN restoration and PIK3CB knockdown synergistically suppress glioblastoma growth in vitro and in xenografts Chen, Hongbo Mei, Lin Zhou, Lanzhen Shen, Xiaomeng Guo, Caiping Zheng, Yi Zhu, Huijun Zhu, Yongqiang Huang, Laiqiang J. Neurooncol. 104:155-67 21478295 Pubmed 2011 PIK3R1 (p85?) is somatically mutated at high frequency in primary endometrial cancer Urick, Mary E Rudd, Meghan L Godwin, Andrew K Sgroi, Dennis Merino, Maria Bell, Daphne W Cancer Res. 71:4061-7 21984976 Pubmed 2011 High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability Cheung, Lydia W T Hennessy, Bryan T Li, Jie Yu, Shuangxing Myers, Andrea P Djordjevic, Bojana Lu, Yiling Stemke-Hale, Katherine Dyer, Mary D Zhang, Fan Ju, Zhenlin Cantley, Lewis C Scherer, Steven E Liang, Han Lu, Karen H Broaddus, Russell R Mills, Gordon B Cancer Discov 1:170-85 19644473 Pubmed 2009 Targeting the phosphoinositide 3-kinase pathway in cancer Liu, Pixu Cheng, Hailing Roberts, Thomas M Zhao, Jean J Nat Rev Drug Discov 8:627-44 22120714 Pubmed 2011 Regulation of lipid binding underlies the activation mechanism of class IA PI3-kinases Hon, W-C Berndt, A Williams, R L Oncogene 18594509 Pubmed 2008 Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis Jia, Shidong Liu, Zhenning Zhang, Sen Liu, Pixu Zhang, Lei Lee, Sang Hyun Zhang, Jing Signoretti, Sabina Loda, Massimo Roberts, Thomas M Zhao, Jean J Nature 454:776-9 16339315 Pubmed 2005 The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells Zhao, Jean J Liu, Zhenning Wang, L Shin, Eyoung Loda, Massimo F Roberts, Thomas M Proc. Natl. Acad. Sci. U.S.A. 102:18443-8 18079394 Pubmed 2007 The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations Huang, Chuan-Hsiang Mandelker, Diana Schmidt-Kittler, Oleg Samuels, Y Velculescu, VE Kinzler, KW Vogelstein, B Gabelli, Sandra B Amzel, L Mario Science 318:1744-8 20713702 Pubmed 2010 Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha Sun, Minghao Hillmann, Petra Hofmann, Bianca T Hart, Jonathan R Vogt, Peter K Proc. Natl. Acad. Sci. U.S.A. 107:15547-52 20231295 Pubmed 2010 Phosphoinositide 3-kinase pathway activation in phosphate and tensin homolog (PTEN)-deficient prostate cancer cells is independent of receptor tyrosine kinases and mediated by the p110beta and p110delta catalytic subunits Jiang, Xinnong Chen, Sen Asara, John M Balk, Steven P J. Biol. Chem. 285:14980-9 17626883 Pubmed 2007 Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit Miled, Nabil Yan, Ying Hon, Wai-Ching Perisic, O Zvelebil, Marketa Inbar, Yuval Schneidman-Duhovny, Dina Wolfson, Haim J Backer, Jonathan M Williams, RL Science 317:239-42 18317450 Pubmed 2008 Mutations in the catalytic subunit of class IA PI3K confer leukemogenic potential to hematopoietic cells Horn, S Bergholz, U Jücker, M McCubrey, J A Trümper, L Stocking, C Bäsecke, J Oncogene 27:4096-106 19185485 Pubmed 2009 PI 3-kinase and cancer: changing accents Vogt, Peter K Gymnopoulos, Marco Hart, Jonathan R Curr. Opin. Genet. Dev. 19:12-7 18755892 Pubmed 2008 PTEN-deficient cancers depend on PIK3CB Wee, Susan Wiederschain, Dmitri Maira, Sauveur-Michel Loo, Alice Miller, Christine deBeaumont, Rosalie Stegmeier, Frank Yao, Yung-Mae Lengauer, Christoph Proc. Natl. Acad. Sci. U.S.A. 105:13057-62 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 PI3K inhibitors block PI3K catalytic activity PI3K inhibitors block PI3K catalytic activity A variety of inhibitors capable of blocking the phosphoinositide kinase activity of PI3K have been developed. These inhibitors display differential selectivity and inhibit kinase activity of their substrates by distinct mechanisms. For example, the first-generation PI3K inhibitor wortmannin (Wymann et al. 1996) covalently and irreversibly binds all classes of PI3K enzymes, as well as other kinases including mTOR, at a residue critical for catalytic activity. Although wortmannin is precluded from in vivo and clinical use due to its toxicity, it has proven to be a useful tool for in vitro laboratory studies. Newer inhibitors, such as BEZ235, are currently being investigated in Phase I clinical trials. BEZ235 is a dual pan-class I PI3K/mTOR inhibitor that blocks kinase activity by binding competitively to the ATP-binding pocket of these enzymes (Serra et al. 2008, Maira et al. 2008). BGT226 (Chang et al. 2011) and XL765 (Prasad et al. 2011) also inhibits both PI3K class I enzymes and mTOR. Other inhibitors in clinical trials, such as BKM120 (Maira et al. 2012), GDC0941 (Folkes et al. 2008, Junttila et al. 2009) and XL147 (Chakrabarty et al. 2012), are specific for class I PI3Ks and exhibit no activity against mTOR. Current research aims to identify isoform-specific PI3K inhibitors. Small molecule inhibitors that selectively inhibit PIK3CA (p110alpha), e.g. PIK-75 and A66, were used to study the role of p110alpha in signaling and growth of tumor cells (Knight et al. 2006, Sun et al. 2010, Jamieson et al. 2011, Utermark et al. 2012). The PIK3CB (p110beta) specific inhibitor TGX221 has been used in in vitro models of vascular injury (Jackson et al. 2005), and the TGX221 derivative KIN-193 has been shown to block AKT activity and tumor growth in mice with p110beta activation or PTEN loss (Ni et al. 2012). CAL-101 is a PIK3CD (p110delta) specific inhibitor that is being clinically investigated as a therapeutic for lymphoid malignancies (Herman et al. 2010). It is hoped that, in the future, more specific inhibitors, such as those targeting selective PI3K isoforms, will provide optimum treatment while minimizing unwanted side effects. For a recent review, please refer to Liu et al. 2009. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Converted from EntitySet in Reactome Reactome DB_ID: 2399811 1 PI3K/mutant PI3K inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity BKM120 [cytosol] GDC0941 [cytosol] XL147 [cytosol] PX-866 [cytosol] LY294002 [cytosol] wortmannin [cytosol] BGT226 [cytosol] BEZ235 [cytosol] XL765 [cytosol] Guide to Pharmacology 7878 Guide to Pharmacology 5682 Guide to Pharmacology 7963 Guide to Pharmacology 7941 Guide to Pharmacology 6004 Guide to Pharmacology 6060 Guide to Pharmacology 7951 Guide to Pharmacology 7950 Guide to Pharmacology 7964 Converted from EntitySet in Reactome Reactome DB_ID: 2400011 1 PI3K mutants,Activator:PI3K [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 2400008 1 PI3K Inhibitors:PI3K [cytosol] PI3K Inhibitors:PI3K Converted from EntitySet in Reactome Reactome DB_ID: 2399811 1 Converted from EntitySet in Reactome Reactome DB_ID: 2400011 1 Homo sapiens NCBI Taxonomy 9606 Reactome Database ID Release 82 2400008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2400008 Reactome R-HSA-2400008 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2400008.1 Reactome Database ID Release 82 2400009 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2400009 Reactome R-HSA-2400009 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2400009.2 18754654 Pubmed 2008 The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer Folkes, Adrian J Ahmadi, Khatereh Alderton, Wendy K Alix, Sonia Baker, Stewart J Box, Gary Chuckowree, Irina S Clarke, Paul A Depledge, Paul Eccles, Suzanne A Friedman, Lori S Hayes, Angela Hancox, Timothy C Kugendradas, Arumugam Lensun, Letitia Moore, Pauline Olivero, Alan G Pang, Jodie Patel, Sonal Pergl-Wilson, Giles H Raynaud, Florence I Robson, Anthony Saghir, Nahid Salphati, Laurent Sohal, Sukhjit Ultsch, Mark H Valenti, Melanie Wallweber, Heidi J A Wan, Nan Chi Wiesmann, C Workman, Paul Zhyvoloup, A Zvelebil, Marketa J Shuttleworth, Stephen J J. Med. Chem. 51:5522-32 21976531 Pubmed 2011 Novel phosphoinositide 3-kinase/mTOR dual inhibitor, NVP-BGT226, displays potent growth-inhibitory activity against human head and neck cancer cells in vitro and in vivo Chang, Kwang-Yu Tsai, Shan-Yin Wu, Ching-Ming Yen, Chia-Jui Chuang, Bin-Fay Chang, Jang-Yang Clin. Cancer Res. 17:7116-26 21668414 Pubmed 2011 A drug targeting only p110? can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types Jamieson, Stephen Flanagan, Jack U Kolekar, Sharada Buchanan, Christina Kendall, Jackie D Lee, Woo-Jeong Rewcastle, Gordon W Denny, William A Singh, Ripudaman Dickson, James Baguley, Bruce C Shepherd, Peter R Biochem. J. 438:53-62 20522708 Pubmed 2010 Phosphatidylinositol 3-kinase-? inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals Herman, Sarah E M Gordon, Amber L Wagner, Amy J Heerema, Nyla A Zhao, Weiqiang Flynn, Joseph M Jones, Jeffrey Andritsos, Leslie Puri, Kamal D Lannutti, Brian J Giese, Neill A Zhang, Xiaoli Wei, Lai Byrd, John C Johnson, Amy J Blood 116:2078-88 22802530 Pubmed 2012 The p110? and p110? isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis Utermark, Tamara Rao, Trisha Cheng, Hailing Wang, Qi Lee, Sang Hyun Wang, Zhigang C Iglehart, J Dirk Roberts, Thomas M Muller, William J Zhao, Jean J Genes Dev. 26:1573-86 21368164 Pubmed 2012 Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors Chakrabarty, Anindita Sánchez, Violeta Kuba, María G Rinehart, Cammie Arteaga, Carlos L Proc. Natl. Acad. Sci. U.S.A. 109:2718-23 15834429 Pubmed 2005 PI 3-kinase p110beta: a new target for antithrombotic therapy Jackson, Shaun P Schoenwaelder, Simone M Goncalves, Isaac Nesbitt, Warwick S Yap, Cindy L Wright, Christine E Kenche, Vijaya Anderson, Karen E Dopheide, Sacha M Yuan, Yuping Sturgeon, Sharelle A Prabaharan, Hishani Thompson, Philip E Smith, Gregg D Shepherd, Peter R Daniele, Nathalie Kulkarni, S Abbott, Belinda Saylik, Dilek Jones, Catherine Lu, Lucy Giuliano, Simon Hughan, Sascha C Angus, James A Robertson, Alan D Salem, Hatem H Nat. Med. 11:507-14 18829560 Pubmed 2008 NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations Serra, Violeta Markman, Ben Scaltriti, Maurizio Eichhorn, Pieter J A Valero, Vanesa Guzman, Marta Botero, Maria Luisa Llonch, Elisabeth Atzori, Francesco Di Cosimo, Serena Maira, Michel Garcia-Echeverria, Carlos Parra, Josep Lluis Arribas, Joaquin Baselga, J Cancer Res. 68:8022-30 22588880 Pubmed 2012 Functional characterization of an isoform-selective inhibitor of PI3K-p110? as a potential anticancer agent Ni, Jing Liu, Qingsong Xie, Shaozhen Carlson, Coby Von, Thanh Vogel, Kurt Riddle, Steve Benes, Cyril Eck, Michael Roberts, Thomas Gray, Nathanael S Zhao, Jean Cancer Discov 2:425-33 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 16647110 Pubmed 2006 A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling Knight, Zachary A Gonzalez, Beatriz Feldman, Morri E Zunder, Eli R Goldenberg, David D Williams, Olusegun Loewith, Robbie Stokoe, David Balla, Andras Toth, Balazs Balla, Tamas Weiss, William A Williams, RL Shokat, Kevan M Cell 125:733-47 21317208 Pubmed 2011 Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide Prasad, Gautam Sottero, Theo Yang, Xiaodong Mueller, Sabine James, C David Weiss, William A Polley, Mei-Yin Ozawa, Tomoko Berger, Mitchel S Aftab, Dana T Prados, Michael D Haas-Kogan, Daphne A Neuro-oncology 13:384-92 18606717 Pubmed 2008 Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity Maira, Sauveur-Michel Stauffer, Frédéric Brueggen, Josef Furet, Pascal Schnell, Christian Fritsch, Christine Brachmann, Saskia Chène, Patrick De Pover, Alain Schoemaker, Kevin Fabbro, D Gabriel, Daniela Simonen, Marjo Murphy, Leon Finan, Peter Sellers, William García-Echeverría, Carlos Mol. Cancer Ther. 7:1851-63 22188813 Pubmed 2012 Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor Maira, Sauveur-Michel Pecchi, Sabina Huang, Alan Burger, Matthew Knapp, Mark Sterker, Dario Schnell, Christian Guthy, Daniel Nagel, Tobi Wiesmann, M Brachmann, Saskia Fritsch, Christine Dorsch, Marion Chène, Patrick Shoemaker, Kevin De Pover, Alain Menezes, Daniel Martiny-Baron, Georg Fabbro, D Wilson, Christopher J Schlegel, Robert Hofmann, F García-Echeverría, Carlos Sellers, William R Voliva, Charles F Mol. Cancer Ther. 11:317-28 8657148 Pubmed 1996 Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction Wymann, Matthias Bulgarelli-Leva, Ginette Zvelebil, Marketa Pirola, Luciano Vanhaesebroeck, Bart Waterfield, Michael Panayotou, George Mol. Cell. Biol. 16:1722-33 Reactome Database ID Release 82 2219530 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2219530 Reactome R-HSA-2219530 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2219530.1 20009532 Pubmed 2010 Hot-spot mutations in p110alpha of phosphatidylinositol 3-kinase (pI3K): differential interactions with the regulatory subunit p85 and with RAS Zhao, Li Vogt, Peter K Cell Cycle 9:596-600 Constitutive Signaling by AKT1 E17K in Cancer Constitutive Signaling by AKT1 E17K in Cancer While AKT1 gene copy number, expression level and phosphorylation are often increased in cancer, only one low frequency point mutation has been repeatedly reported in cancer and functionally studied. This mutation represents a substitution of a glutamic acid residue with lysine at position 17 of AKT1, and acts by enabling AKT1 to bind PIP2. PIP2-bound AKT1 is phosphorylated by TORC2 complex and by PDPK1 that is always present at the plasma membrane, due to low affinity for PIP2. Therefore, E17K substitution abrogates the need for PI3K in AKT1 activation (Carpten et al. 2007, Landgraf et al. 2008). Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 AKT1 E17K mutant binds PIP2 AKT1 E17K mutant binds PIP2 Substitution of glutamic acid with lysine at position 17 of AKT1 results in constitutive plasma membrane localization of AKT1, independent of PI3K activity and PIP3 generation (Carpten et al. 2007). This constitutive plasma membrane targeting of AKT1 E17K mutant is due to an increased affinity for PIP2 (Landgraf et al. 2008). Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 179856 1 Reactome DB_ID: 2219526 1 UniProt:P31749 AKT1 AKT1 RAC PKB AKT1 FUNCTION AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (By similarity). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (By similarity). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (PubMed:11994271). AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity (By similarity). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (By similarity). AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase) (PubMed:11154276). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis (PubMed:11154276). AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating the TORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1 (PubMed:12150915). Also regulates the TORC1 signaling pathway by catalyzing phosphorylation of CASTOR1 (PubMed:33594058). AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization (PubMed:10358075). In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319' (PubMed:10358075). FOXO3 and FOXO4 are phosphorylated on equivalent sites (PubMed:10358075). AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein) (PubMed:9829964). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1 (PubMed:9829964). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (By similarity). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) (PubMed:12176338, PubMed:12964941). AKT mediates the antiapoptotic effects of IGF-I (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). May be involved in the regulation of the placental development (By similarity). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3 (PubMed:17726016). Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation (PubMed:20086174, PubMed:20231902). Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (PubMed:19592491). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity (PubMed:10576742). Phosphorylation of BAD stimulates its pro-apoptotic activity (PubMed:10926925). Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 (PubMed:23431171). Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility (PubMed:20471940). Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation (PubMed:18507042). Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization (PubMed:16982699). These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation (PubMed:16139227). Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (PubMed:20682768). Phosphorylates PCK1 at 'Ser-90', reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor (PubMed:32322062). Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity (PubMed:32228865).ACTIVITY REGULATION Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation (PubMed:20481595, PubMed:21392984, PubMed:9512493, PubMed:9736715). Inhibited by pyrrolopyrimidine inhibitors like aniline triazole and spiroindoline (PubMed:18456494, PubMed:20810279).SUBUNIT Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts (via the C-terminus) with CCDC88A (via its C-terminus). Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE-binding (By similarity). Interacts with AGAP2 (isoform 2/PIKE-A); the interaction occurs in the presence of guanine nucleotides. Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with CDKN1B; the interaction phosphorylates CDKN1B promoting 14-3-3 binding and cell-cycle progression. Interacts with MAP3K5 and TRAF6. Interacts with BAD, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with RAF1. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with TNK2 and CLK2. Interacts (via the C-terminus) with THEM4 (via its C-terminus). Interacts with and phosphorylated by PDPK1. Interacts with PA2G4 (By similarity). Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation (PubMed:24784001). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529). Forms a complex with WDFY2 and FOXO1 (By similarity). Interacts with FAM168A (PubMed:23251525). Interacts with SYAP1 (via phosphorylated form and BSD domain); this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1 (PubMed:23300339). Interacts with PKHM3 (By similarity). Interacts with FKBP5/FKBP51; promoting interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1 (PubMed:28147277). Interacts with TMEM175; leading to formation of the lysoK(GF) complex (PubMed:32228865). Acts as a negative regulator of the cGAS-STING pathway by mediating phosphorylation of CGAS during mitosis, leading to its inhibition (PubMed:26440888).TISSUE SPECIFICITY Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages.DOMAIN Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction.DOMAIN The AGC-kinase C-terminal mediates interaction with THEM4.PTM O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1. O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site.PTM Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity (PubMed:12149249, PubMed:14761976, PubMed:15047712, PubMed:16266983, PubMed:17013611, PubMed:20978158, PubMed:9736715, PubMed:23799035, PubMed:8978681, PubMed:28147277). Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA (PubMed:20333297). This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation (PubMed:9512493). Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1 (PubMed:21464307, PubMed:8978681). Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1 (PubMed:15718470, PubMed:18456494, PubMed:20481595, PubMed:8978681). Ser-473 phosphorylation is enhanced by interaction with AGAP2 isoform 2 (PIKE-A) (PubMed:14761976). Ser-473 phosphorylation is enhanced in focal cortical dysplasias with Taylor-type balloon cells (PubMed:17013611). Ser-473 phosphorylation is enhanced by signaling through activated FLT3 (By similarity). Ser-473 is dephosphorylated by PHLPP (PubMed:28147277). Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase (PubMed:21329884). The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase (PubMed:21329884). Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (PubMed:9512493).PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation (PubMed:19713527). When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated (PubMed:20059950). When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome (PubMed:20059950). Also ubiquitinated by TRIM13 leading to its proteasomal degradation (PubMed:21333377). Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation (PubMed:22410793). Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome (By similarity).PTM Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition.PTM Cleavage by caspase-3/CASP3 (By similarity). Cleaved at the caspase-3 consensus site Asp-462 during apoptosis, resulting in down-regulation of the AKT signaling pathway and decreased cell survival (PubMed:23152800).DISEASE Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION PUBMED:19940129 has been retracted because the same data were used to represent different experimental conditions.CAUTION In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain. UniProt P31749 L-glutamic acid 17 replaced with L-lysine 17 EQUAL L-glutamic acid removal [MOD:01636] Chain Coordinates 1 EQUAL 480 EQUAL Reactome DB_ID: 2219527 1 AKT1 E17K mutant:PIP2 [plasma membrane] AKT1 E17K mutant:PIP2 Reactome DB_ID: 179856 1 Reactome DB_ID: 1500573 1 L-glutamic acid 17 replaced with L-lysine 17 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2219527 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2219527 Reactome R-HSA-2219527 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2219527.1 Reactome Database ID Release 82 2219536 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2219536 Reactome R-HSA-2219536 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2219536.2 17611497 Pubmed 2007 A transforming mutation in the pleckstrin homology domain of AKT1 in cancer Carpten, JD Faber, AL Horn, C Donoho, GP Briggs, SL Robbins, CM Hostetter, G Boguslawski, S Moses, TY Savage, S Uhlik, M Lin, A Du, J Qian, YW Zeckner, DJ Tucker-Kellogg, G Touchman, J Patel, K Mousses, S Bittner, M Schevitz, R Lai, MHT Blanchard, KL Thomas, JE Nature 448:439-44 18954143 Pubmed 2008 Molecular mechanism of an oncogenic mutation that alters membrane targeting: Glu17Lys modifies the PIP lipid specificity of the AKT1 PH domain Landgraf, KE Pilling, C Falke, JJ Biochemistry 47:12260-9 2.7.11.1 AKT1 E17K mutant is phosphorylated by TORC2 complex AKT1 E17K mutant is phosphorylated by TORC2 complex PIP2-binding AKT1 E17K mutants are anchored to the plasma membrane in the absence of PI3K activity and are constitutively phosphorylated on serine S473, presumably by the TORC2 complex (Carpten et al. 2007, Landgraf et al. 2008). Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 2219527 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 2243943 1 p-S473-AKT1 E17K mutant:PIP2 [plasma membrane] p-S473-AKT1 E17K mutant:PIP2 Reactome DB_ID: 179856 1 Reactome DB_ID: 2243944 1 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-serine [MOD:00046] 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2243943 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2243943 Reactome R-HSA-2243943 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2243943.1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 198626 TORC2 complex [cytosol] TORC2 complex mTORC2 mTOR2 Reactome DB_ID: 165676 1 UniProt:Q9BVC4 MLST8 MLST8 GBL MLST8 LST8 FUNCTION Subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, LST8 interacts directly with MTOR and enhances its kinase activity. In nutrient-poor conditions, stabilizes the MTOR-RPTOR interaction and favors RPTOR-mediated inhibition of MTOR activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Interacts directly with MTOR and RPTOR. Interacts with RHEB. Interacts with MEAK7 (PubMed:29750193). Interacts with SIK3 (PubMed:30232230).TISSUE SPECIFICITY Broadly expressed, with highest levels in skeletal muscle, heart and kidney.SIMILARITY Belongs to the WD repeat LST8 family. UniProt Q9BVC4 1 EQUAL 326 EQUAL Reactome DB_ID: 165662 1 UniProt:P42345 MTOR MTOR FRAP1 RAFT1 FRAP2 FRAP RAPT1 MTOR FUNCTION Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18925875, PubMed:18497260, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (By similarity). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4 (PubMed:12150925, PubMed:12087098, PubMed:18925875). This also includes mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3: in the presence of nutrients, mediates phosphorylation of TFEB and TFE3, promoting their cytosolic retention and inactivation (PubMed:22576015, PubMed:22343943, PubMed:22692423). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex (PubMed:23429704, PubMed:23429703). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (By similarity). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). mTORC1 also negatively regulates autophagy through phosphorylation of ULK1 (By similarity). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (PubMed:20537536). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (PubMed:30704899). Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA (PubMed:23524951, PubMed:25438055). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (PubMed:21659604). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (PubMed:12231510). As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton (PubMed:15268862, PubMed:15467718). Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1 (PubMed:15718470). mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B (PubMed:15268862). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:18925875). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity). Phosphorylates SQSTM1, promoting interaction between SQSTM1 and KEAP1 and subsequent inactivation of the BCR(KEAP1) complex (By similarity).ACTIVITY REGULATION Activation of mTORC1 by growth factors such as insulin involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase a potent activator of the protein kinase activity of mTORC1. Insulin-stimulated and amino acid-dependent phosphorylation at Ser-1261 promotes autophosphorylation and the activation of mTORC1. Activation by amino acids requires relocalization of the mTORC1 complex to lysosomes that is mediated by the Ragulator complex, SLC38A9, and the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD (PubMed:18497260, PubMed:20381137, PubMed:25561175, PubMed:25567906). On the other hand, low cellular energy levels can inhibit mTORC1 through activation of PRKAA1 while hypoxia inhibits mTORC1 through a REDD1-dependent mechanism which may also require PRKAA1. The kinase activity of MTOR within the mTORC1 complex is positively regulated by MLST8 and negatively regulated by DEPTOR and AKT1S1. MTOR phosphorylates RPTOR which in turn inhibits mTORC1. MTOR is the target of the immunosuppressive and anti-cancer drug rapamycin which acts in complex with FKBP1A/FKBP12, and specifically inhibits its kinase activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. It may be regulated by RHEB but in an indirect manner through the PI3K signaling pathway.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. The mTORC1 complex is a 1 Md obligate dimer of two stoichiometric heterotetramers with overall dimensions of 290 A x 210 A x 135 A. It has a rhomboid shape and a central cavity, the dimeric interfaces are formed by interlocking interactions between the two MTOR and the two RPTOR subunits. The MLST8 subunit forms distal foot-like protuberances, and contacts only one MTOR within the complex, while the small PRAS40 localizes to the midsection of the central core, in close proximity to RPTOR. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Interacts with PLPP7 and PML. Interacts with PRR5 and RICTOR; the interaction is direct within the mTORC2 complex and interaction with RICTOR is enhanced by deubiquitination of RICTOR by USP9X (PubMed:33378666). Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). Interacts with UBQLN1. Interacts with TTI1 and TELO2. Interacts with CLIP1; phosphorylates and regulates CLIP1. Interacts with NBN. Interacts with HTR6 (PubMed:23027611). Interacts with BRAT1. Interacts with MEAK7 (via C-terminal domain); the interaction increases upon nutrient stimulation (PubMed:29750193). Interacts with TM4SF5; the interaction is positively regulated by arginine and is negatively regulated by leucine (PubMed:30956113). Interacts with GPR137B (PubMed:31036939). Interacts with NCKAP1L (PubMed:32647003). Interacts with TPCN1 and TPCN2; the interaction is required for TPCN1 and TPCN2 sensitivity to ATP (PubMed:23394946). Interacts with ATP6V1A and with CRYAB, forming a ternary complex (By similarity).TISSUE SPECIFICITY Expressed in numerous tissues, with highest levels in testis.DOMAIN The kinase domain (PI3K/PI4K) is intrinsically active but has a highly restricted catalytic center.DOMAIN The FAT domain forms three discontinuous subdomains of alpha-helical TPR repeats plus a single subdomain of HEAT repeats. The four domains pack sequentially to form a C-shaped a-solenoid that clamps onto the kinase domain (PubMed:23636326).PTM Autophosphorylates when part of mTORC1 or mTORC2. Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes autophosphorylation. Phosphorylation in the kinase domain modulates the interactions of MTOR with RPTOR and PRAS40 and leads to increased intrinsic mTORC1 kinase activity. Phosphorylation at Thr-2173 in the ATP-binding region by AKT1 strongly reduces kinase activity.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt P42345 1 EQUAL 2549 EQUAL Reactome DB_ID: 3006620 1 UniProt:Q9BPZ7 MAPKAP1 MAPKAP1 MAPKAP1 MIP1 SIN1 FUNCTION Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Within mTORC2, MAPKAP1 is required for complex formation and mTORC2 kinase activity. MAPKAP1 inhibits MAP3K2 by preventing its dimerization and autophosphorylation. Inhibits HRAS and KRAS signaling. Enhances osmotic stress-induced phosphorylation of ATF2 and ATF2-mediated transcription. Involved in ciliogenesis, regulates cilia length through its interaction with CCDC28B independently of mTORC2 complex.SUBUNIT All isoforms except isoform 4 can be incorporated into the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (PubMed:16962653, PubMed:16919458, PubMed:33378666). Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Interacts with ATF2, MAP3K2 and MAPK8. Interacts with GTP-bound HRAS and KRAS. Interacts with IFNAR2 and SGK1. Isoform 2 interacts with NBN. Isoform 1 interacts with CCDC28B.TISSUE SPECIFICITY Ubiquitously expressed, with highest levels in heart and skeletal muscle.SIMILARITY Belongs to the SIN1 family. UniProt Q9BPZ7 2 EQUAL 522 EQUAL Reactome DB_ID: 6795323 1 UniProt:P85299 PRR5 PRR5 PRR5 PROTOR1 PP610 FUNCTION Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. PRR5 plays an important role in regulation of PDGFRB expression and in modulation of platelet-derived growth factor signaling. May act as a tumor suppressor in breast cancer.SUBUNIT Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Binds directly to MTOR and RICTOR within the TORC2 complex.TISSUE SPECIFICITY Most abundant in kidney and liver. Also highly expressed in brain, spleen, testis and placenta. Overexpressed in several colorectal tumors.SIMILARITY Belongs to the PROTOR family. UniProt P85299 1 EQUAL 388 EQUAL Reactome DB_ID: 198632 1 UniProt:Q6R327 RICTOR RICTOR KIAA1999 RICTOR FUNCTION Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Plays an essential role in embryonic growth and development.SUBUNIT Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (PubMed:15268862, PubMed:15467718, PubMed:17461779, PubMed:17599906). Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Binds directly to MTOR and PRR5 within the TORC2 complex; interaction with MTOR is enhanced by deubiquitination of RICTOR by USP9X (PubMed:15268862, PubMed:17461779, PubMed:17599906, PubMed:33378666). Interaction with MAPKAP1 is not enhanced by RICTOR deubiquitination by USP9X (PubMed:33378666). Interacts with CCDC28B (PubMed:23727834). Interacts with NBN (PubMed:23762398). Interacts with PRR5L (PubMed:17461779, PubMed:21964062). Interacts with SIK3 (PubMed:30232230). Interacts with NCKAP1L (PubMed:32647003). Interacts with kinases GSK3A and GSK3B; the interactions lead to phosphorylation of RICTOR at 'Thr-1695' which facilitates its FBXW7-mediated ubiquitination and subsequent degradation (PubMed:25897075). Interacts with FBXW7; the interaction is enhanced by GSK3-mediated phosphorylation of 'Thr-1695' and results in RICTOR ubiquitination and degradation (PubMed:25897075). Interacts with USP9X; the interaction results in deubiquitination of RICTOR and protection from proteasomal degradation, thus promoting mTORC2 complex assembly (PubMed:33378666).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein F17; this interaction dysregulates mTOR.PTM Phosphorylated by MTOR; when part of mTORC2 (PubMed:15467718). Phosphorylated at Thr-1135 by RPS6KB1; phosphorylation of RICTOR inhibits mTORC2 and AKT1 signaling (PubMed:19995915). Phosphorylated at Thr-1695 by GSK3A and GSK3B which facilitates RICTOR ubiquitination and subsequent degradation (PubMed:25897075).PTM Ubiquitinated by the SCF(FBXW7) complex, leading to its degradation by the proteasome (PubMed:25897075). Deubiquitinated by USP9X; deubiquitination stabilizes RICTOR and enhances its binding to MTOR, thus promoting mTORC2 complex assembly (PubMed:33378666).SIMILARITY Belongs to the RICTOR family. UniProt Q6R327 1 EQUAL 1708 EQUAL Reactome Database ID Release 82 198626 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198626 Reactome R-HSA-198626 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198626.2 GO 0004674 GO molecular function Reactome Database ID Release 82 198624 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198624 Reactome Database ID Release 82 2243938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2243938 Reactome R-HSA-2243938 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2243938.2 PIP2-bound p-S473-AKT1 mutant binds PIP2-bound PDPK1 PIP2-bound p-S473-AKT1 mutant binds PIP2-bound PDPK1 A portion of PDPK1 (PDK1) is anchored to the plasma membrane in the absence of PI3K activity through PIP2 binding (Currie et al. 1999). This PIP2-bound PDPK1 is able to bind and phosphorylate PIP2-bound AKT E17K mutants (Carpten et al. 2007, Landgraf et al. 2008) phosphorylated on serine residue S473. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 2243943 1 Reactome DB_ID: 2219520 1 PDPK1:PIP2 [plasma membrane] PDPK1:PIP2 Reactome DB_ID: 179856 1 Reactome DB_ID: 61459 1 UniProt:O15530 PDPK1 PDPK1 PDPK1 PDK1 FUNCTION Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive.ACTIVITY REGULATION Homodimerization regulates its activity by maintaining the kinase in an autoinhibitory conformation. NPRL2 down-regulates its activity by interfering with tyrosine phosphorylation at the Tyr-9, Tyr-373 and Tyr-376 residues. The 14-3-3 protein YWHAQ acts as a negative regulator by association with the residues surrounding the Ser-241 residue. STRAP positively regulates its activity by enhancing its autophosphorylation and by stimulating its dissociation from YWHAQ. SMAD2, SMAD3, SMAD4 and SMAD7 also positively regulate its activity by stimulating its dissociation from YWHAQ. Activated by phosphorylation on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin.SUBUNIT Homodimer in its autoinhibited state. Active as monomer. Interacts with NPRL2, PPARG, PAK1, PTK2B, GRB14, PKN1 (via C-terminus), STRAP and IKKB. The Tyr-9 phosphorylated form interacts with SRC, RASA1 and CRK (via their SH2 domains). Interacts with SGK3 in a phosphorylation-dependent manner. The tyrosine-phosphorylated form interacts with PTPN6. The Ser-241 phosphorylated form interacts with YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH domain) with SMAD3, SMAD4 and SMAD7. Interacts with PKN2; the interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-dependent kinase activity toward 'Ser-473' of AKT1 but also activates its kinase activity toward PRKCD and PRKCZ.TISSUE SPECIFICITY Appears to be expressed ubiquitously. The Tyr-9 phosphorylated form is markedly increased in diseased tissue compared with normal tissue from lung, liver, colon and breast.INDUCTION Stimulated by insulin, and the oxidants hydrogen peroxide and peroxovanadate.DOMAIN The PH domain plays a pivotal role in the localization and nuclear import of PDPK1 and is also essential for its homodimerization.DOMAIN The PIF-pocket is a small lobe in the catalytic domain required by the enzyme for the binding to the hydrophobic motif of its substrates. It is an allosteric regulatory site that can accommodate small compounds acting as allosteric inhibitors.PTM Phosphorylation on Ser-241 in the activation loop is required for full activity. PDPK1 itself can autophosphorylate Ser-241, leading to its own activation. Autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2 (By similarity). Tyr-9 phosphorylation is critical for stabilization of both PDPK1 and the PDPK1/SRC complex via HSP90-mediated protection of PDPK1 degradation. Angiotensin II stimulates the tyrosine phosphorylation of PDPK1 in vascular smooth muscle in a calcium- and SRC-dependent manner. Phosphorylated on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin. Palmitate negatively regulates autophosphorylation at Ser-241 and palmitate-induced phosphorylation at Ser-529 and Ser-501 by PKC/PRKCQ negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylation at Thr-354 by MELK partially inhibits kinase activity, the inhibition is cooperatively enhanced by phosphorylation at Ser-394 and Ser-398 by MAP3K5.PTM Autophosphorylated; autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2.PTM Monoubiquitinated in the kinase domain, deubiquitinated by USP4.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PDPK1 subfamily. UniProt O15530 1 EQUAL 556 EQUAL Reactome Database ID Release 82 2219520 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2219520 Reactome R-HSA-2219520 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2219520.1 Reactome DB_ID: 2243941 1 PDPK1:p-S473-AKT1 E17K mutant:PIP2 [plasma membrane] PDPK1:p-S473-AKT1 E17K mutant:PIP2 Reactome DB_ID: 2243943 1 Reactome DB_ID: 2219520 1 Reactome Database ID Release 82 2243941 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2243941 Reactome R-HSA-2243941 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2243941.1 Reactome Database ID Release 82 2243937 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2243937 Reactome R-HSA-2243937 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2243937.2 9895304 Pubmed 1999 Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1 Currie, RA Walker, KS Gray, A Deak, M Casamayor, A Downes, CP Cohen, P Alessi, DR Lucocq, J Biochem J 337:575-83 2.7.11.1 PDPK1 phosphorylates AKT1 E17K mutant PDPK1 phosphorylates AKT1 E17K mutant PIP2-bound AKT1 E17K mutant is constitutively phosphorylated on threonine residue T308 (Carpten et al. 2007, Landgraf et al. 2008), presumably by PIP2-bound PDPK1 (Currie et al. 1999). Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 2243941 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 2243935 1 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL O-phospho-L-threonine [MOD:00047] 1 EQUAL 480 EQUAL Reactome DB_ID: 2219520 1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2243941 Reactome Database ID Release 82 2243940 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2243940 Reactome Database ID Release 82 2243942 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2243942 Reactome R-HSA-2243942 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2243942.2 2.7.11.1 AKT1 E17K mutant phosphorylates GSK3 AKT1 E17K mutant phosphorylates GSK3 AKT1 E17K gain-of-function mutant preserves the ability to phosphorylate GSK3 (Malanga et al. 2008). AKT-mediated phosphorylation inactivates GSK3 and enables WNT-independent stabilization of beta-catenin (CTNNB1) (Haq et al. 2003). AKT-mediated inactivation of GSK3 also triggers changes in glucose metabolism (Ueki et al. 1997). Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 113592 1 Converted from EntitySet in Reactome Reactome DB_ID: 198358 1 GSK3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GSK3B [cytosol] GSK3A [cytosol] UniProt P49841 UniProt P49840 Converted from EntitySet in Reactome Reactome DB_ID: 198373 1 p-S9/21-GSK3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-S21-GSK3A [cytosol] p-S9-GSK3B [cytosol] Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2243935 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399974 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399974 Reactome Database ID Release 82 2399966 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399966 Reactome R-HSA-2399966 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399966.1 18256540 Pubmed 2008 Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung Malanga, Donatella Scrima, Marianna De Marco, Carmela Fabiani, Fernanda De Rosa, Nicla De Gisi, Silvia Malara, Natalia Savino, Rocco Rocco, Gaetano Chiappetta, Gennaro Franco, Renato Tirino, Virginia Pirozzi, Giuseppe Viglietto, Giuseppe Cell Cycle 7:665-9 12668767 Pubmed 2003 Stabilization of beta-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth Haq, Syed Michael, Ashour Andreucci, Michele Bhattacharya, Kausik Dotto, Paolo Walters, Brian Woodgett, James Kilter, Heiko Force, Thomas Proc. Natl. Acad. Sci. U.S.A. 100:4610-5 9478990 Pubmed 1998 Potential role of protein kinase B in insulin-induced glucose transport, glycogen synthesis, and protein synthesis Ueki, K Yamamoto-Honda, R Kaburagi, Y Yamauchi, T Tobe, K Burgering, B M Coffer, P J Komuro, I Akanuma, Y Yazaki, Y Kadowaki, T J. Biol. Chem. 273:5315-22 2.7.11.1 AKT1 E17K mutant phosphorylates p21Cip1 and p27Kip1 AKT1 E17K mutant phosphorylates p21Cip1 and p27Kip1 AKT1 E17K gain-of-function mutant preserves the ability to phosphorylate CDKN1B i.e. p27Kip1 (Malanga et al. 2008) and is expected to phosphorylate CDKN1A i.e. p21Cip1, like the wild-type AKT (Viglietto et al. 2002), although this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Converted from EntitySet in Reactome Reactome DB_ID: 182504 1 CDKN1A,CDKN1B [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CDKN1B [cytosol] CDKN1A [cytosol] UniProt P46527 UniProt P38936 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Converted from EntitySet in Reactome Reactome DB_ID: 198605 1 p-T-CDKN1A/B [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-T157-CDKN1B [cytosol] p-T145-CDKN1A [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2243935 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399969 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399969 Reactome R-HSA-2399969 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399969.2 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 2.7.11.1 AKT1 E17K mutant phosphorylates BAD AKT1 E17K mutant phosphorylates BAD AKT1 E17K gain-of-function mutant phosphorylates BAD (Guo et al. 2010). AKT-mediated BAD phosphorylation inactivates BAD, thereby preventing BAD-mediated apoptosis (Del Peso et al. 1997). Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 50662 1 UniProt:Q92934 BAD BAD BCL2L8 BAD BBC6 FUNCTION Promotes cell death. Successfully competes for the binding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the level of heterodimerization of these proteins with BAX. Can reverse the death repressor activity of Bcl-X(L), but not that of Bcl-2 (By similarity). Appears to act as a link between growth factor receptor signaling and the apoptotic pathways.SUBUNIT Forms heterodimers with the anti-apoptotic proteins, Bcl-X(L), Bcl-2 and Bcl-W. Also binds protein S100A10 (By similarity). The Ser-75/Ser-99 phosphorylated form binds 14-3-3 proteins (By similarity). Interacts with AKT1 and PIM3. Interacts (via BH3 domain) with NOL3 (via CARD domain); preventing the association of BAD with BCL2 (By similarity). Interacts with HIF3A (via C-terminus domain); the interaction reduces the binding between BAD and BAX (By similarity). Interacts with GIMAP3/IAN4 and GIMAP5/IAN5 (PubMed:16509771).TISSUE SPECIFICITY Expressed in a wide variety of tissues.DOMAIN Intact BH3 motif is required by BIK, BID, BAK, BAD and BAX for their pro-apoptotic activity and for their interaction with anti-apoptotic members of the Bcl-2 family.PTM Phosphorylated on one or more of Ser-75, Ser-99, Ser-118 and Ser-134 in response to survival stimuli, which blocks its pro-apoptotic activity. Phosphorylation on Ser-99 or Ser-75 promotes heterodimerization with 14-3-3 proteins. This interaction then facilitates the phosphorylation at Ser-118, a site within the BH3 motif, leading to the release of Bcl-X(L) and the promotion of cell survival. Ser-99 is the major site of AKT/PKB phosphorylation, Ser-118 the major site of protein kinase A (CAPK) phosphorylation. Phosphorylation at Ser-99 by PKB/AKT1 is almost completely blocked by the apoptotic C-terminus cleavage product of PKN2 generated by caspases-3 activity during apoptosis.PTM Methylation at Arg-94 and Arg-96 by PRMT1 inhibits Akt-mediated phosphorylation at Ser-99.SIMILARITY Belongs to the Bcl-2 family.CAUTION The protein name 'Bcl2 antagonist of cell death' may be misleading. The protein antagonises Bcl2-mediated repression of cell death, hence it promotes apoptosis. UniProt Q92934 1 EQUAL 168 EQUAL Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 198335 1 O-phospho-L-serine at 99 99 EQUAL 1 EQUAL 168 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2243935 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399941 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399941 Reactome R-HSA-2399941 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399941.1 9381178 Pubmed 1997 Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt del Peso, L Gonzalez-Garcia, M Page, Clive P Herrera, R Nunez, G Science 278:687-9 20440266 Pubmed 2010 Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells Guo, G Qiu, X Wang, S Chen, Y Rothman, P B Wang, Z Chen, Y Wang, G Chen, J-L Oncogene 29:3845-53 2.7.11.1 AKT1 E17K mutant phosphorylates AKT1S1 (PRAS40) AKT1 E17K mutant phosphorylates AKT1S1 (PRAS40) AKT1 E17K gain-of-function mutant is expected to phosphorylate AKT1S1 (PRAS40), like the wild-type AKT (Kovacina et al. 2003), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 200155 1 UniProt:Q96B36 AKT1S1 AKT1S1 PRAS40 AKT1S1 FUNCTION Subunit of mTORC1, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, AKT1S1 negatively regulates mTOR activity in a manner that is dependent on its phosphorylation state and binding to 14-3-3 proteins. Inhibits RHEB-GTP-dependent mTORC1 activation. Substrate for AKT1 phosphorylation, but can also be activated by AKT1-independent mechanisms. May also play a role in nerve growth factor-mediated neuroprotection.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin. Interacts directly with RPTOR. The phosphorylated form interacts with 14-3-3 proteins.TISSUE SPECIFICITY Widely expressed with highest levels of expression in liver and heart. Expressed at higher levels in cancer cell lines (e.g. A-549 and HeLa) than in normal cell lines (e.g. HEK293).PTM Phosphorylated by AKT1 (PubMed:12524439). Phosphorylation at Thr-246 by DYRK3 relieves inhibitory function on mTORC1 (PubMed:23415227). UniProt Q96B36 1 EQUAL 256 EQUAL Reactome DB_ID: 113592 2 Reactome DB_ID: 200163 1 O-phospho-L-serine at 183 183 EQUAL O-phospho-L-threonine at 246 246 EQUAL 1 EQUAL 256 EQUAL Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2243935 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399977 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399977 Reactome R-HSA-2399977 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399977.1 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 2.7.11.1 AKT1 E17K mutant phosphorylates MDM2 AKT1 E17K mutant phosphorylates MDM2 AKT1 E17K gain-of-function mutant is expected to phosphorylate MDM2, like the wild-type AKT (Zhou et al. 2001, Feng et al. 2004, Milne et al. 2004), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 198644 1 UniProt:Q00987 MDM2 MDM2 MDM2 FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also a component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation (PubMed:12821780, PubMed:15053880, PubMed:15195100, PubMed:15632057, PubMed:16337594, PubMed:17290220, PubMed:19098711, PubMed:19219073, PubMed:19837670, PubMed:19965871, PubMed:20173098, PubMed:20385133, PubMed:20858735, PubMed:22128911). Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells (By similarity). Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis (By similarity). Negatively regulates NDUFS1, leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis (PubMed:30879903). Binds NDUFS1 leading to its cytosolic retention rather than mitochondrial localization resulting in decreased supercomplex assembly (interactions between complex I and complex III), decreased complex I activity, ROS production, and apoptosis (PubMed:30879903).SUBUNIT Interacts with p53/TP53, TP73/p73, RBL5 and RP11. Binds specifically to RNA. Can interact with RB1, E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with p53/TP53 and WWOX. Interacts with CDKN2AIP, RFWD3, USP7, PYHIN1, and RBBP6. Interacts with ARRB1 and ARRB2. Interacts with PSMA3. Found in a trimeric complex with MDM2, MDM4 and USP2. Interacts with USP2 (via N-terminus and C-terminus). Interacts with MDM4. Part of a complex with MDM2, DAXX, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7. Interacts directly with DAXX and USP7. Interacts (via C-terminus) with RASSF1 isoform A (via N-terminus); the interaction is independent of TP53. Interacts with APEX1; leading to its ubiquitination and degradation. Interacts with RYBP; this inhibits ubiquitination of TP53. Identified in a complex with RYBP and p53/TP53. Also a component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in regulating p53/TP53 stabilization and activity. Binds directly both p53/TP53 and TRIM28. Component of the TRIM28/KAP1-ERBB4-MDM2 complex involved in connecting growth factor responses with DNA damage. Interacts directly with both TRIM28 and ERBB4 in the complex. Interacts with DYRK2. Interacts with IGF1R. Interacts with TRIM13; the interaction ubiquitinates MDM2 leading to its proteasomal degradation. Interacts with SNAI1; this interaction promotes SNAI1 ubiquitination. Interacts with NOTCH1 (via intracellular domain). Interacts with FHIT. Interacts with RFFL and RNF34; the interaction stabilizes MDM2. Interacts with CDK5RAP3 and CDKN2A/ARF; form a ternary complex involved in regulation of p53/TP53 (PubMed:16173922). Interacts with MTA1. Interacts with AARB2. Interacts with MTBP. Interacts with PML. Interacts with TBRG1. Interacts with the 5S RNP which is composed of the 5S RNA, RPL5 and RPL11; the interaction is direct, occurs in the nucleoplasm and negatively regulates MDM2-mediated TP53 ubiquitination and degradation (PubMed:15195100, PubMed:24120868). Interacts with ADGRB1; the interaction results in inhibition of MDM2-mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4 stability and regulating synaptic plasticity (By similarity). Interacts with RPL23A; this interaction may promote p53/TP53 polyubiquitination (PubMed:26203195). Interacts with NDUFS1 (PubMed:30879903).SUBUNIT (Microbial infection) Interacts with herpes virus 8 protein v-IRF4.SUBUNIT (Microbial infection) Interacts with and ubiquitinates HIV-1 Tat.TISSUE SPECIFICITY Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues.INDUCTION By DNA damage.DOMAIN Region I is sufficient for binding p53 and inhibiting its G1 arrest and apoptosis functions. It also binds p73 and E2F1. Region II contains most of a central acidic region required for interaction with ribosomal protein L5 and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc interacts specifically with RNA whether or not zinc is present and mediates the heterooligomerization with MDM4. It is also essential for its ubiquitin ligase E3 activity toward p53 and itself.PTM Phosphorylation on Ser-166 by SGK1 activates ubiquitination of p53/TP53. Phosphorylated at multiple sites near the RING domain by ATM upon DNA damage; this prevents oligomerization and E3 ligase processivity and impedes constitutive p53/TP53 degradation.PTM Autoubiquitination leads to proteasomal degradation; resulting in p53/TP53 activation it may be regulated by SFN. Also ubiquitinated by TRIM13. Deubiquitinated by USP2 leads to its accumulation and increases deubiquitination and degradation of p53/TP53. Deubiquitinated by USP7 leading to its stabilization.POLYMORPHISM A polymorphism in the MDM2 promoter is associated with susceptibility to accelerated tumor formation in both hereditary and sporadic cancers [MIM:614401]. It also contributes to susceptibility to Li-Fraumeni syndrome, in patients carrying a TP53 germline mutation.DISEASE Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.MISCELLANEOUS MDM2 RING finger mutations that failed to ubiquitinate p53 in vitro did not target p53 for degradation when expressed in cells.SIMILARITY Belongs to the MDM2/MDM4 family.CAUTION Was reported to interact with UBXN6 but the corresponding article has been retracted (PubMed:18768758).CAUTION A report observed N-glycosylation at Asn-349 (PubMed:19139490). However, as the protein is not extracellular, additional evidence is required to confirm this result. UniProt Q00987 1 EQUAL 491 EQUAL Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 198638 1 O-phospho-L-serine at 166 166 EQUAL O-phospho-L-serine at 188 188 EQUAL 1 EQUAL 491 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2243935 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399981 Reactome R-HSA-2399981 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399981.1 15169778 Pubmed 2004 Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation Feng, Jianhua Tamaskovic, Rastislav Yang, Zhongzhou Brazil, Derek P Merlo, Adrian Hess, Daniel Hemmings, BA J. Biol. Chem. 279:35510-7 15527798 Pubmed 2004 A novel site of AKT-mediated phosphorylation in the human MDM2 onco-protein Milne, Diane Kampanis, Petros Nicol, Samantha Dias, Sylvia Campbell, David G Fuller-Pace, Frances Meek, David FEBS Lett. 577:270-6 11715018 Pubmed 2001 HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation Zhou, BP Liao, Y Xia, W Zou, Y Spohn, B Hung, MC Nat Cell Biol 3:973-82 2.7.11.1 AKT1 E17K mutant phosphorylates TSC2, inhibiting it AKT1 E17K mutant phosphorylates TSC2, inhibiting it AKT1 E17K gain-of-function mutant is expected to phosphorylate TSC2 and inhibit it, like the wild-type AKT (Inoki et al. 2002, Manning et al. 2002), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 2980548 1 UniProt:P49815 TSC2 TSC2 TSC4 TSC2 FUNCTION In complex with TSC1, this tumor suppressor inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400). Acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 (PubMed:15340059). May also play a role in microtubule-mediated protein transport (By similarity). Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 (By similarity).SUBUNIT Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex thereby stabilizing TSC2 (PubMed:29127155). Interacts with TSC1 and HERC1; the interaction with TSC1 stabilizes TSC2 and prevents the interaction with HERC1 (PubMed:9580671, PubMed:10585443, PubMed:15963462, PubMed:16464865). May also interact with the adapter molecule RABEP1 (PubMed:9045618). The final complex may contain TSC2 and RABEP1 linked to RAB5 (PubMed:9045618). Interacts with HSPA1 and HSPA8 (PubMed:15963462). Interacts with DAPK1 (PubMed:18974095). Interacts with FBXW5 (PubMed:18381890). Interacts with NAA10 (via C-terminal domain) (PubMed:20145209). Interacts with RRAGA (polyubiquitinated) (PubMed:25936802). Interacts with WDR45B (PubMed:28561066). Interacts with RPAP3 and URI1 (PubMed:28561026). Interacts with YWHAG (PubMed:33473107).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL38; this interaction inhibits cellular stress response mediated by mTORC1.TISSUE SPECIFICITY Liver, brain, heart, lymphocytes, fibroblasts, biliary epithelium, pancreas, skeletal muscle, kidney, lung and placenta.PTM Phosphorylation at Ser-1387, Ser-1418 or Ser-1420 does not affect interaction with TSC1. Phosphorylation at Ser-939 and Thr-1462 by PKB/AKT1 is induced by growth factor stimulation. Phosphorylation by AMPK activates it and leads to negative regulation of the mTORC1 complex. Phosphorylated at Ser-1798 by RPS6KA1; phosphorylation inhibits TSC2 ability to suppress mTORC1 signaling. Phosphorylated by DAPK1.PTM Ubiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase complex, leading to its subsequent degradation. Ubiquitinated by MYCBP2 independently of its phosphorylation status leading to subsequent degradation; association with TSC1 protects from ubiquitination. UniProt P49815 1 EQUAL 1807 EQUAL Reactome DB_ID: 113592 2 Reactome DB_ID: 199484 1 O-phospho-L-serine at 939 939 EQUAL O-phospho-L-threonine at 1462 1462 EQUAL 1 EQUAL 1807 EQUAL Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2243935 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399982 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399982 Reactome R-HSA-2399982 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399982.1 12150915 Pubmed 2002 Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway Manning, BD Tee, AR Logsdon, MN Blenis, J Cantley, Lewis C Mol Cell 10:151-62 12172553 Pubmed 2002 TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling Inoki, K Li, Yun Zhu, T Wu, J Guan, KL Nat Cell Biol 4:648-57 2.7.11.1 AKT1 E17K mutant phosphorylates CHUK (IKKalpha) AKT1 E17K mutant phosphorylates CHUK (IKKalpha) AKT1 E17K gain-of-function mutant is expected to phosphorylate CHUK (IKKalpha), like the wild-type AKT (Ozes et al. 1999), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 113592 1 Reactome DB_ID: 168104 1 UniProt:O15111 CHUK CHUK TCF16 CHUK IKKA FUNCTION Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11) (PubMed:21765415). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes (PubMed:20501937). In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities (PubMed:17434128). Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP (PubMed:12789342). Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates AMBRA1 following mitophagy induction, promoting AMBRA1 interaction with ATG8 family proteins and its mitophagic activity (PubMed:30217973).ACTIVITY REGULATION Activated when phosphorylated and inactivated when dephosphorylated.SUBUNIT Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits (PubMed:32935379). The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:10195894, PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Directly interacts with TRPC4AP (By similarity). May interact with TRAF2 (PubMed:19150425). Interacts with NALP2 (PubMed:15456791). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity (PubMed:20434986). Interacts with PIAS1; this interaction induces PIAS1 phosphorylation (PubMed:17540171). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with FOXO3 (PubMed:15084260). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14 (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Directly interacts with DDX3X after the physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation (PubMed:30341167).SUBUNIT (Microbial infection) Interacts with InlC of Listeria monocytogenes.TISSUE SPECIFICITY Widely expressed.DOMAIN The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.PTM Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.PTM (Microbial infection) Acetylation of Thr-179 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. UniProt O15111 1 EQUAL 745 EQUAL Reactome DB_ID: 29370 1 Reactome DB_ID: 198615 1 O-phospho-L-threonine at 23 23 EQUAL 1 EQUAL 745 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2243935 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2400001 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2400001 Reactome R-HSA-2400001 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2400001.1 10485710 Pubmed 1999 NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase Ozes, ON Mayo, LD Gustin, JA Pfeffer, SR Pfeffer, LM Donner, DB Nature 401:82-5 2.7.11.1 AKT1 E17K mutant phosphorylates caspase-9 AKT1 E17K mutant phosphorylates caspase-9 AKT1 E17K gain-of-function mutant is expected to phosphorylate caspase-9 (CASP9), like the wild-type AKT (Cardone et al. 1998), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 57033 1 UniProt:P55211 CASP9 CASP9 CASP9 MCH6 FUNCTION Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates caspase-3. Promotes DNA damage-induced apoptosis in a ABL1/c-Abl-dependent manner. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP).FUNCTION Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9.ACTIVITY REGULATION Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis.SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 35 kDa (p35) and a 10 kDa (p10) subunit. Caspase-9 and APAF1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome C and ATP. Interacts (inactive form) with EFHD2. Interacts with HAX1. Interacts with BIRC2/c-IAP1, XIAP/BIRC4, BIRC5/survivin, BIRC6/bruce and BIRC7/livin. Interacts with ABL1 (via SH3 domain); the interaction is direct and increases in the response of cells to genotoxic stress and ABL1/c-Abl activation. Interacts with BCL2L10 (PubMed:19255499). Interacts with NleF from pathogenic E.coli.TISSUE SPECIFICITY Ubiquitous, with highest expression in the heart, moderate expression in liver, skeletal muscle, and pancreas. Low levels in all other tissues. Within the heart, specifically expressed in myocytes.DEVELOPMENTAL STAGE Expressed at low levels in fetal heart, at moderate levels in neonate heart, and at high levels in adult heart.PTM Cleavages at Asp-315 by granzyme B and at Asp-330 by caspase-3 generate the two active subunits. Caspase-8 and -10 can also be involved in these processing events.PTM Phosphorylated at Thr-125 by MAPK1/ERK2. Phosphorylation at Thr-125 is sufficient to block caspase-9 processing and subsequent caspase-3 activation. Phosphorylation on Tyr-153 by ABL1/c-Abl; occurs in the response of cells to DNA damage.SIMILARITY Belongs to the peptidase C14A family. UniProt P55211 1 EQUAL 416 EQUAL Reactome DB_ID: 113592 1 Reactome DB_ID: 198636 1 O-phospho-L-serine at 196 196 EQUAL 1 EQUAL 416 EQUAL Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2243935 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399985 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399985 Reactome R-HSA-2399985 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399985.2 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 AKT1 E17K mutant translocates to the nucleus AKT1 E17K mutant translocates to the nucleus AKT1 E17K gain-of-function mutant is expected to translocate to the nucleus, like the wild-type AKT (Borgatti et al. 2003), but this has not been directly experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 2243935 1 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome DB_ID: 2399994 1 nucleoplasm GO 0005654 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399997 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399997 Reactome R-HSA-2399997 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399997.2 12767043 Pubmed 2003 Threonine 308 phosphorylated form of Akt translocates to the nucleus of PC12 cells under nerve growth factor stimulation and associates with the nuclear matrix protein nucleolin Borgatti, P Martelli, AM Tabellini, G Bellacosa, A Capitani, S Neri, LM J Cell Physiol 196:79-88 2.7.11.1 AKT1 E17K mutant phosphorylates forkhead box transcription factors AKT1 E17K mutant phosphorylates forkhead box transcription factors AKT1 E17K gain-of-function mutant phosphorylates FOXO3 (Carpten et al. 2007), and is expected to phosphorylate other forkhead box transcription factor family members, FOXO1 and FOXO4, and possibly FOXO6, like the wild-type AKT (Brunet et al. 1999, Rena et al. 1999, Matsuzaki et al. 2005), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 29358 3 Converted from EntitySet in Reactome Reactome DB_ID: 199272 1 FOXO1,FOXO3,FOXO4,(FOXO6) [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity FOXO4 [nucleoplasm] FOXO3 [nucleoplasm] FOXO1 [nucleoplasm] UniProt P98177 UniProt O43524 UniProt Q12778 Reactome DB_ID: 113582 3 Converted from EntitySet in Reactome Reactome DB_ID: 9614997 1 p-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4,(p-T26,S184-FOXO6) [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-T32,S253,S315-FOXO3 [nucleoplasm] p-T32,S197,S262-FOXO4 [nucleoplasm] p-T24,S256,S319-FOXO1 [nucleoplasm] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2399994 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399993 Reactome Database ID Release 82 2399992 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399992 Reactome R-HSA-2399992 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399992.2 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 16272144 Pubmed 2005 Regulation of intracellular localization and transcriptional activity of FOXO4 by protein kinase B through phosphorylation at the motif sites conserved among the FOXO family Matsuzaki, H Ichino, A Hayashi, T Yamamoto, T Kikkawa, U J Biochem (Tokyo) 138:485-91 10358075 Pubmed 1999 Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B Rena, G Guo, S Cichy, SC Unterman, TG Cohen, P J Biol Chem 274:17179-83 2.7.11.1 AKT1 E17K mutant phosphorylates CREB1 AKT1 E17K mutant phosphorylates CREB1 AKT1 E17K gain-of-function mutant is expected to phosphorylate CREB1, like the wild-type AKT (Du et al. 1998), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 29358 1 Reactome DB_ID: 52777 1 UniProt:P16220 CREB1 CREB1 CREB1 FUNCTION Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-119 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.SUBUNIT Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. When phosphorylated on Ser-119, binds CREBBP (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity (By similarity). Interacts (phosphorylated form) with TOX3. Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119 (PubMed:15964553). Forms a complex with KMT2A and CREBBP (PubMed:23651431, PubMed:14506290, PubMed:14536081, PubMed:15454081, PubMed:15733869, PubMed:15964553, PubMed:16325578, PubMed:16908542, PubMed:20573984, PubMed:21172805) (By similarity). Interacts with TOX4; CREB1 is required for full induction of TOX4-dependent activity and the interaction is increased by cAMP and inhibited by insulin (By similarity).SUBUNIT (Microbial infection) Interacts with hepatitis B virus/HBV protein X.SUBUNIT (Microbial infection) Interacts with HTLV-1 protein Tax.PTM Stimulated by phosphorylation. Phosphorylation of both Ser-119 and Ser-128 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylation of Ser-119 allows CREBBP binding. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion (By similarity). CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity (By similarity). Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-119. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of Ser-128 blocks CREB-mediated transcription even when Ser-119 is phosphorylated. Phosphorylated by CaMK1 (By similarity). Phosphorylation of Ser-257 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. Phosphorylated by TSSK4 on Ser-119 (PubMed:15964553).PTM Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization.DISEASE A CREB1 mutation has been found in a patient with multiple congenital anomalies consisting of agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia.SIMILARITY Belongs to the bZIP family. UniProt P16220 1 EQUAL 341 EQUAL Reactome DB_ID: 113582 1 Reactome DB_ID: 111910 1 O-phospho-L-serine at 133 133 EQUAL 1 EQUAL 341 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2399994 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399996 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399996 Reactome R-HSA-2399996 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399996.1 9829964 Pubmed 1998 CREB is a regulatory target for the protein kinase Akt/PKB Du, K Montminy, M J Biol Chem 273:32377-9 2.7.11.1 AKT1 E17K mutant phosphorylates RSK AKT1 E17K mutant phosphorylates RSK AKT1 E17K gain-of-function mutant is expected to phosphorylate ribosomal protein S6 kinase beta-2, like the wild-type AKT (Koh et al. 1999), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 29358 2 Reactome DB_ID: 199877 1 UniProt:Q9UBS0 RPS6KB2 RPS6KB2 STK14B RPS6KB2 FUNCTION Phosphorylates specifically ribosomal protein S6 (PubMed:29750193). Seems to act downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression in an alternative pathway regulated by MEAK7 (PubMed:29750193).PTM Phosphorylated and activated by MTOR. Phosphorylation by PKC within the NLS in response to mitogenic stimuli causes cytoplasmic retention.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily. UniProt Q9UBS0 1 EQUAL 482 EQUAL Reactome DB_ID: 113582 2 Reactome DB_ID: 199844 1 O-phospho-L-serine at 15 15 EQUAL O-phospho-L-serine at 356 356 EQUAL 1 EQUAL 482 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2399994 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399999 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399999 Reactome R-HSA-2399999 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399999.1 10490848 Pubmed 1999 Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); a novel nuclear target of Akt Koh, H Jee, K Lee, B Kim, J Kim, D Yun, YH Kim, JW Choi, HS Chung, J Oncogene 18:5115-9 2.7.11.1 AKT1 E17K mutant phosphorylates NR4A1 (NUR77) AKT1 E17K mutant phosphorylates NR4A1 (NUR77) AKT1 E17K gain-of-function mutant is expected to phosphorylate NR4A1, like the wild-type AKT (Pekarsky et al. 2001), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Reactome DB_ID: 29358 1 Reactome DB_ID: 199831 1 UniProt:P22736 NR4A1 NR4A1 NR4A1 HMR GFRP1 NAK1 FUNCTION Orphan nuclear receptor. May act concomitantly with NURR1 in regulating the expression of delayed-early genes during liver regeneration. Binds the NGFI-B response element (NBRE) 5'-AAAAGGTCA-3' (By similarity). May inhibit NF-kappa-B transactivation of IL2. Participates in energy homeostasis by sequestrating the kinase STK11 in the nucleus, thereby attenuating cytoplasmic AMPK activation. Plays a role in the vascular response to injury (By similarity).SUBUNIT Binds DNA as a monomer (By similarity). Interacts with GADD45GIP1 (PubMed:15459248). Interacts with STK11 (PubMed:22983157). Interacts with IFI27 (PubMed:22427340). Heterodimer (via DNA-binding domain) with RXRA (via C-terminus); DNA-binding of the heterodimer is enhanced by 9-cis retinoic acid (PubMed:17761950, PubMed:15509776). Competes for the RXRA interaction with EP300 and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950).TISSUE SPECIFICITY Fetal muscle and adult liver, brain and thyroid.INDUCTION By growth-stimulating agents.PTM Phosphorylated at Ser-351 by RPS6KA1 and RPS6KA3 in response to mitogenic or stress stimuli.PTM Acetylated by p300/CBP, acetylation increases stability. Deacetylated by HDAC1.SIMILARITY Belongs to the nuclear hormone receptor family. NR4 subfamily. UniProt P22736 1 EQUAL 598 EQUAL Reactome DB_ID: 199846 1 O-phospho-L-serine at 351 351 EQUAL 1 EQUAL 598 EQUAL Reactome DB_ID: 113582 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2399994 L-glutamic acid 17 replaced with L-lysine 17 EQUAL O-phospho-L-serine at 473 473 EQUAL O-phospho-L-threonine at 308 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 82 2399988 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2399988 Reactome R-HSA-2399988 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2399988.1 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 AKT inhibitors block AKT membrane recruitment AKT inhibitors block AKT membrane recruitment AKT inhibitors bind AKT and prevent its association with the membrane, thereby blocking AKT activation (Kondapaka et al. 2003, Yap et al. 2011, Berndt et al. 2010). AKT inhibitors annotated here target all AKT isoforms (AKT1, AKT2 and AKT3). None of the annotated inhibitors are AKT E17K mutant specific and none of them have been approved for clinical use. For a recent review, please refer to Liu et al. 2009. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Converted from EntitySet in Reactome Reactome DB_ID: 2399923 1 AKT inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity perifosine [cytosol] MK2206 [cytosol] Triciribine [cytosol] Guide to Pharmacology 7424 Guide to Pharmacology 7945 Guide to Pharmacology 5920 Converted from EntitySet in Reactome Reactome DB_ID: 2400013 1 AKT/AKT1 E17K mutant [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AKT1 [cytosol] Reactome DB_ID: 2400006 1 AKT inhibitors:AKT [cytosol] AKT inhibitors:AKT Converted from EntitySet in Reactome Reactome DB_ID: 2399923 1 Converted from EntitySet in Reactome Reactome DB_ID: 2400013 1 Reactome Database ID Release 82 2400006 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2400006 Reactome R-HSA-2400006 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2400006.1 Reactome Database ID Release 82 2400010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2400010 Reactome R-HSA-2400010 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2400010.1 22025163 Pubmed 2011 First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors Yap, Timothy A Yan, Li Patnaik, Amita Fearen, Ivy Olmos, David Papadopoulos, Kyriakos Baird, Richard D Delgado, Liliana Taylor, Adekemi Lupinacci, Lisa Riisnaes, Ruth Pope, Lorna L Heaton, Simon P Thomas, George Garrett, Michelle D Sullivan, Daniel M de Bono, JS Tolcher, Anthony W J. Clin. Oncol. 29:4688-95 20489726 Pubmed 2010 The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane Berndt, N Yang, H Trinczek, B Betzi, S Zhang, Z Wu, B Lawrence, N J Pellecchia, M Schönbrunn, E Cheng, J Q Sebti, S M Cell Death Differ. 17:1795-804 14617782 Pubmed 2003 Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation Kondapaka, Sudhir B Singh, Sheo S Dasmahapatra, Girija P Sausville, Edward A Roy, Krishnendu K Mol. Cancer Ther. 2:1093-103 Reactome Database ID Release 82 5674400 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5674400 Reactome R-HSA-5674400 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5674400.1 PTEN Loss of Function in Cancer PTEN Loss of Function in Cancer Loss-of-function mutations affecting the phosphatase domain of PTEN are frequently found in sporadic cancers (Kong et al. 1997, Lee et al. 1999, Han et al. 2000), as well as in PTEN hamartoma tumor syndromes (PHTS) (Marsh et al. 1998). PTEN can also be inactivated by gene deletion or epigenetic silencing, or indirectly by overexpression of microRNAs that target PTEN mRNA (Huse et al. 2009). Cells with deficient PTEN function have increased levels of PIP3, and therefore increased AKT activity. For a recent review, please refer to Hollander et al. 2011. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 3.1.3.67 PTEN cancer mutants do not dephosphorylate PIP3 PTEN cancer mutants do not dephosphorylate PIP3 One of the functions of PTEN is to act as a phosphoinositide phosphatase that catalyzes dephosphorylation of PIP3 into PIP2. PTEN thus reduces the amount of available PIP3, counteracting PI3K activity and downregulating AKT signaling. PTEN is frequently targeted by loss of function mutations in cancer and in familial cancer syndromes known as PTHS (PTEN hamartoma tumor syndromes, a collection of diseases including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Lhermitte-Duclos disease). Some PTEN loss-of-function variants are also found in autism spectrum disorder patients. For a recent review of PTEN involvement in cancer, please refer to Hollander et al. 2011. <br> <br>The majority of missense mutations that impair phosphoinositide phosphatase activity of PTEN cluster in exon 5 of PTEN gene and result in substitution of amino acid residues in the catalytic cleft of the phosphatase domain. Arginine at position 130 is the most frequently substituted PTEN residue in cancer. R130 of human PTEN is the last arginine residue in the conserved H-C-K/R-A-G-K-G-R sequence (corresponding to HCXXGXXR motif of protein tyrosine phosphatases) in the catalytic cleft of the PTEN phosphatase domain and is essential for catalysis (Barford et al. 1994, Lee et al. 1999). PTEN R130 substitution mutants show markedly decreased phosphoinositide phosphatase activity (Han et al. 2000, Koul et al. 2002) and are frequently found in endometrial carcinoma (Kong et al. 1997, Konopka et al. 2007). The cysteine residue at position 124 (C124) of human PTEN, in the conserved H-C-K/R-A-G-K-G-R sequence, 'attacks' the phosphate group of a substrate and forms a thio-phosphate intermediate during the dephosphorylation reaction (Guan and Dixon 1991, Barford et al. 1994, Lee et al. 1999). Therefore, substitution of this critical C124 abolishes PTEN phosphatase activity (Han et al. 2000, Koul et al. 2002). Substitution of histidine H123 in the conserved H-C-K/R-A-G-K-G-R sequence also impairs PTEN phosphatase activity (Lee et al. 1999).<br><br>Missense mutations also target amino acid residues in the N-terminal phosphatase domain that are outside the catalytic cleft. Substitution of histidine at position 93 affects the conserved WPD loop of the phosphatase domain of PTEN, and PTEN H93 mutants show low phosphoinositide phosphatase activity (Lee et al. 1999). Serine residue S170 and histidine residue H173 participate in the formation of hydrogen bonds between the N-terminal phosphatase domain of PTEN and the C-terminal membrane-binding C2 domain (Lee et al. 1999). H173, and to a lesser extent S170, are targeted by missense mutations in cancer, and substitution mutants have impaired phosphoinositide phosphatase activity (Han et al. 2000). <br><br>Missense mutations also occur in the C2 domain of PTEN. The C2 domain is implicated in membrane binding and localization of PTEN, but also in PTEN roles unrelated to its phosphoinositide phosphatase function (Raftopoulou et al. 2004). Since the roles of these C2 domain PTEN mutants in cancer have not been clarified, these variants will be annotated when more information becomes available. <br><br>Besides missense mutations, nonsense mutations that result in PTEN protein truncation are also frequently found in cancer samples. The three residues most frequently targeted by nonsense mutations are R130, R233 and R335. While R130* mutation directly affects the phosphatase domain of PTEN, R233* and R335* affect the C2 domain. PTEN 130*, PTEN R233* and PTEN R335* mutants have not been functionally studied, but it was shown that comparable PTEN truncation mutants generated by directed mutagenesis, PTEN-254 and PTEN-342, were unstable when expressed in human cells and had severely diminished phosphatase activity in vitro (Georgescu et al. 1999). <br>Cancer-derived PTEN truncation mutants whose phosphatase domain (amino acid residues 14-185) is absent or partially truncated are annotated as truncation mutant set members (PTEN E7*, PTEN R11*, PTEN K13*, PTEN Q17*, PTEN E18*, PTEN G20*, PTEN L23*, PTEN Y27*, PTEN E40*, PTEN E43*, PTEN Y46*, PTEN S59*, PTEN K62*, PTEN Y65*, PTEN Y68*, PTEN E73*, PTEN R84*, PTEN Y88*, PTEN E91*, PTEN Q97*, PTEN E99*, PTEN C105*, PTEN Q110*, PTEN W111*, PTEN E114*, PTEN K125*, PTEN G127*, PTEN K128*, PTEN G129*, PTEN R130*, PTEN Y138*, PTEN L139*, PTEN L146*, PTEN K147*, PTEN Q149*, PTEN E150*, PTEN E157*, PTEN K163*, PTEN G165*, PTEN Q171*, PTEN Y174*, PTEN Y176*, PTEN Y177*, PTEN Y178*, PTEN Y180*, PTEN L182*).<br>Cancer-derived PTEN truncation mutants whose phosphatase domain is intact but whose C2 tensin-type domain (amino acids 190-350), responsible for interaction with membrane phospholipids and for the overall protein conformation (Lee et al. 1999), is missing or partially truncated are annotated as truncation mutant set candidates (PTEN R189*, PTEN G209*, PTEN C211*, PTEN Q214*, PTEN C218*, PTEN Q219*, PTEN K221*, PTEN Y225*, PTEN S229*, PTEN G230*, PTEN R233*, PTEN E235*, PTEN Y240*, PTEN E242*, PTEN Q245*, PTEN L247*, PTEN C250*, PTEN E256*, PTEN Q261*, PTEN K263*, PTEN W274*, PTEN E284*, PTEN S287*, PTEN E288*, PTEN E291*, PTEN G293*, PTEN C296*, PTEN Q298*, PTEN E299*, PTEN E307*, PTEN E314*, PTEN L320*, PTEN K330*, PTEN K332*, PTEN R335*, PTEN Y336*, PTEN K344*, PTEN Y346*).<br><br>In cancer, PTEN is also frequently inactivated by genomic deletions and loss of heterozygosity (LOH) affecting chromosome band 10q23 or by epigenetic silencing (reviewed by Hollander et al. 2011). Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Reviewed: D'Eustachio, Peter, 2019-09-11 Edited: Matthews, L, 2012-08-03 Edited: Orlic-Milacic, Marija, 2019-08-27 Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 179838 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2317393 PTEN Mutants [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PTEN E114* [cytosol] PTEN R130L [cytosol] PTEN C105* [cytosol] PTEN Y88* [cytosol] PTEN R130Q [cytosol] PTEN G127* [cytosol] PTEN L23* [cytosol] PTEN E73* [cytosol] PTEN G129E [cytosol] PTEN H93Q [cytosol] PTEN Y68* [cytosol] PTEN K13* [cytosol] PTEN L182* [cytosol] PTEN E157* [cytosol] PTEN Y174* [cytosol] PTEN K125* [cytosol] PTEN Y27* [cytosol] PTEN S170N [cytosol] PTEN Y65* [cytosol] PTEN K128* [cytosol] PTEN H93A [cytosol] PTEN E40* [cytosol] PTEN R84* [cytosol] PTEN Y180* [cytosol] PTEN R173H [cytosol] PTEN E7* [cytosol] PTEN H123Y [cytosol] PTEN R130G [cytosol] PTEN E43* [cytosol] PTEN Q110* [cytosol] PTEN R11* [cytosol] PTEN C124S [cytosol] PTEN H93Y [cytosol] PTEN R173P [cytosol] PTEN S170R [cytosol] PTEN K147* [cytosol] PTEN E99* [cytosol] PTEN C124R [cytosol] PTEN G129R [cytosol] PTEN Y138* [cytosol] PTEN S59* [cytosol] PTEN E18* [cytosol] PTEN G165* [cytosol] PTEN Q171* [cytosol] PTEN E150* [cytosol] PTEN G129* [cytosol] PTEN Y176* [cytosol] PTEN Y46* [cytosol] PTEN L146* [cytosol] PTEN Q149* [cytosol] PTEN Y177* [cytosol] PTEN L139* [cytosol] PTEN H93D [cytosol] PTEN H93R [cytosol] PTEN Q17* [cytosol] PTEN G20* [cytosol] PTEN E91* [cytosol] PTEN K163* [cytosol] PTEN K62* [cytosol] PTEN R173C [cytosol] PTEN R130* [cytosol] PTEN Y178* [cytosol] PTEN Q97* [cytosol] PTEN W111* [cytosol] UniProt P60484 GO 0016314 GO molecular function Reactome Database ID Release 82 2317396 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2317396 Reactome Database ID Release 82 2317387 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2317387 Reactome R-HSA-2317387 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2317387.4 1654322 Pubmed 1991 Evidence for protein-tyrosine-phosphatase catalysis proceeding via a cysteine-phosphate intermediate Guan, K L Dixon, Jack J. Biol. Chem. 266:17026-30 14976311 Pubmed 2004 Regulation of cell migration by the C2 domain of the tumor suppressor PTEN Raftopoulou, Myrto Etienne-Manneville, Sandrine Self, Annette Nicholls, Sarah Hall, Alan Science 303:1179-81 10468583 Pubmed 1999 The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region Georgescu, M M Kirsch, K H Akagi, T Shishido, T Hanafusa, H Proc. Natl. Acad. Sci. U.S.A. 96:10182-7 10866302 Pubmed 2000 Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay Han, SY Kato, H Kato, S Suzuki, T Shibata, H Ishii, S Shiiba, K Matsuno, S Kanamaru, R Ishioka, C Cancer Res 60:3147-51 11948419 Pubmed 2002 Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity Koul, Dimpy Jasser, Samar A Lu, Yiling Davies, Michael A Shen, Ruijun Shi, Yuexi Mills, Gordon B Yung, W K Alfred Oncogene 21:2357-64 9326929 Pubmed 1997 PTEN1 is frequently mutated in primary endometrial carcinomas Kong, Dehe Suzuki, Akihiko Zou, Tong-Tong Sakurada, Akira Kemp, Lawrence Wakatsuki, Shigeru Yokoyama, Tadaaki Yamakawa, Hiromitsu Furukawa, Toru Sato, Masami Ohuchi, Noriaki Sato, Shinji Yin, Jing Wang, Suna Abraham, John Souza, Rhonda Smolinski, Kara Meltzer, Stephen Horii, Akira Nat. Genet. 17:143-4 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 21430697 Pubmed 2011 PTEN loss in the continuum of common cancers, rare syndromes and mouse models Hollander, M Christine Blumenthal, Gideon M Dennis, Phillip A Nat. Rev. Cancer 11:289-301 8128219 Pubmed 1994 Crystal structure of human protein tyrosine phosphatase 1B Barford, D Flint, A J Tonks, N K Science 263:1397-404 17219201 Pubmed 2007 Molecular genetic defects in endometrial carcinomas: microsatellite instability, PTEN and beta-catenin (CTNNB1) genes mutations Konopka, Bozena Janiec-Jankowska, Aneta Czapczak, Dorota Paszko, Zygmunt Bidziński, Mariusz Olszewski, Włodzimierz Goluda, Cyprian J. Cancer Res. Clin. Oncol. 133:361-71 Reactome Database ID Release 82 5674404 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5674404 Reactome R-HSA-5674404 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5674404.1 19487573 Pubmed 2009 The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo Huse, Jason T Brennan, Cameron Hambardzumyan, Dolores Wee, Boyoung Pena, John Rouhanifard, Sara H Sohn-Lee, Cherin le Sage, Carlos Agami, Reuven Tuschl, Thomas Holland, Eric C Genes Dev. 23:1327-37 9467011 Pubmed 1998 Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation Marsh, Debbie Coulon, Valérie Lunetta, Kathryn Rocca-Serra, Philippe Dahia, Patricia Zheng, Zimu Liaw, Danny Caron, Stacey Duboué, Bernadette Lin, Albert Richardson, Anne-Louise Bonnetblanc, Jean-Marie Bressieux, Jean-Marie Cabarrot-Moreau, Agnés Chompret, Agnés Demange, Liliane Eeles, Rosalind Yahanda, Alan Fearon, ER Fricker, Jean-Pierre Gorlin, Robert Hodgson, Shirley Huson, Susan Lacombe, Didier Eng, Charis Hum. Mol. Genet. 7:507-15 Reactome Database ID Release 82 2219528 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2219528 Reactome R-HSA-2219528 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2219528.2 17604717 Pubmed 2007 AKT/PKB signaling: navigating downstream Manning, BD Cantley, Lewis C Cell 129:1261-74