ID AKT2_HUMAN Reviewed; 481 AA. AC P31751; B2RBD8; Q05BV0; Q0VAN0; Q0VAN1; Q68GC0; DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1995, sequence version 2. DT 27-MAR-2024, entry version 237. DE RecName: Full=RAC-beta serine/threonine-protein kinase; DE EC=2.7.11.1; DE AltName: Full=Protein kinase Akt-2; DE AltName: Full=Protein kinase B beta; DE Short=PKB beta; DE AltName: Full=RAC-PK-beta; GN Name=AKT2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Epithelium; RX PubMed=1801921; DOI=10.1091/mbc.2.12.1001; RA Jones P.F., Jakubowicz T., Hemmings B.A.; RT "Molecular cloning of a second form of rac protein kinase."; RL Cell Regul. 2:1001-1009(1991). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=1409633; DOI=10.1073/pnas.89.19.9267; RA Cheng J.Q., Godwin A.K., Bellacosa A., Taguchi T., Franke T.F., RA Hamilton T.C., Tsichlis P.N., Testa J.R.; RT "AKT2, a putative oncogene encoding a member of a subfamily of protein- RT serine/threonine kinases, is amplified in human ovarian carcinomas."; RL Proc. Natl. Acad. Sci. U.S.A. 89:9267-9271(1992). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Lymph; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 237-277. RG NIEHS SNPs program; RL Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases. RN [7] RP CHARACTERIZATION, AND PHOSPHORYLATION AT THR-309 BY PDPK1. RX PubMed=9512493; DOI=10.1042/bj3310299; RA Walker K.S., Deak M., Paterson A., Hudson K., Cohen P., Alessi D.R.; RT "Activation of protein kinase B beta and gamma isoforms by insulin in vivo RT and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison RT with protein kinase B alpha."; RL Biochem. J. 331:299-308(1998). RN [8] RP INTERACTION WITH MTCP1; TCL1A AND TCL1B. RX PubMed=10983986; DOI=10.1016/s1097-2765(00)00039-3; RA Laine J., Kuenstle G., Obata T., Sha M., Noguchi M.; RT "The protooncogene TCL1 is an Akt kinase coactivator."; RL Mol. Cell 6:395-407(2000). RN [9] RP MUTAGENESIS OF THR-309 AND SER-474, AND PHOSPHORYLATION AT THR-309 AND RP SER-474. RX PubMed=15890450; DOI=10.1016/j.bbagen.2005.04.002; RA Baer K., Lisinski I., Gompert M., Stuhlmann D., Schmolz K., Klein H.W., RA Al-Hasani H.; RT "Activation of a GST-tagged AKT2/PKBbeta."; RL Biochim. Biophys. Acta 1725:340-347(2005). RN [10] RP INTERACTION WITH WDFY2. RX PubMed=16792529; DOI=10.1042/bj20060511; RA Fritzius T., Burkard G., Haas E., Heinrich J., Schweneker M., Bosse M., RA Zimmermann S., Frey A.D., Caelers A., Bachmann A.S., Moelling K.; RT "A WD-FYVE protein binds to the kinases Akt and PKCzeta/lambda."; RL Biochem. J. 399:9-20(2006). RN [11] RP BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=16540465; DOI=10.1074/jbc.m601384200; RA Zhang X., Zhang S., Yamane H., Wahl R., Ali A., Lofgren J.A., Kendall R.L.; RT "Kinetic mechanism of AKT/PKB enzyme family."; RL J. Biol. Chem. 281:13949-13956(2006). RN [12] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH PBH2. RX PubMed=17565718; DOI=10.1002/jcp.21177; RA Heron-Milhavet L., Mamaeva D., Rochat A., Lamb N.J., Fernandez A.; RT "Akt2 is implicated in skeletal muscle differentiation and specifically RT binds Prohibitin2/REA."; RL J. Cell. Physiol. 214:158-165(2008). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-126, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [14] RP UBIQUITINATION BY TTC3, PHOSPHORYLATION AT THR-309 AND SER-474, AND RP MUTAGENESIS OF THR-309 AND SER-474. RX PubMed=20059950; DOI=10.1016/j.devcel.2009.09.007; RA Suizu F., Hiramuki Y., Okumura F., Matsuda M., Okumura A.J., Hirata N., RA Narita M., Kohno T., Yokota J., Bohgaki M., Obuse C., Hatakeyama S., RA Obata T., Noguchi M.; RT "The E3 ligase TTC3 facilitates ubiquitination and degradation of RT phosphorylated Akt."; RL Dev. Cell 17:800-810(2009). RN [15] RP INTERACTION WITH CLIP3, AND SUBCELLULAR LOCATION. RX PubMed=19139280; DOI=10.1128/mcb.00754-08; RA Ding J., Du K.; RT "ClipR-59 interacts with Akt and regulates Akt cellular RT compartmentalization."; RL Mol. Cell. Biol. 29:1459-1471(2009). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-447; THR-451; SER-474 AND RP SER-478, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [17] RP UBIQUITINATION, AND INTERACTION WITH TRAF6. RX PubMed=19713527; DOI=10.1126/science.1175065; RA Yang W.-L., Wang J., Chan C.-H., Lee S.-W., Campos A.D., Lamothe B., RA Hur L., Grabiner B.C., Lin X., Darnay B.G., Lin H.-K.; RT "The E3 ligase TRAF6 regulates Akt ubiquitination and activation."; RL Science 325:1134-1138(2009). RN [18] RP INVOLVEMENT IN CANCER. RX PubMed=20167810; DOI=10.1093/neuonc/nop026; RA Mure H., Matsuzaki K., Kitazato K.T., Mizobuchi Y., Kuwayama K., Kageji T., RA Nagahiro S.; RT "Akt2 and Akt3 play a pivotal role in malignant gliomas."; RL Neuro-oncol. 12:221-232(2010). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [20] RP REVIEW ON FUNCTION. RX PubMed=21620960; DOI=10.1016/j.cellsig.2011.05.004; RA Hers I., Vincent E.E., Tavare J.M.; RT "Akt signalling in health and disease."; RL Cell. Signal. 23:1515-1527(2011). RN [21] RP REVIEW ON FUNCTION. RX PubMed=21432781; DOI=10.14670/hh-26.651; RA Heron-Milhavet L., Khouya N., Fernandez A., Lamb N.J.; RT "Akt1 and Akt2: differentiating the aktion."; RL Histol. Histopathol. 26:651-662(2011). RN [22] RP FUNCTION IN MUSCLE DIFFERENTIATION, AND INTERACTION WITH ANKRD2. RX PubMed=21737686; DOI=10.1091/mbc.e10-11-0928; RA Cenni V., Bavelloni A., Beretti F., Tagliavini F., Manzoli L., Lattanzi G., RA Maraldi N.M., Cocco L., Marmiroli S.; RT "Ankrd2/ARPP is a novel Akt2 specific substrate and regulates myogenic RT differentiation upon cellular exposure to H(2)O(2)."; RL Mol. Biol. Cell 22:2946-2956(2011). RN [23] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [24] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-34 AND SER-126, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [25] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-34 AND THR-451, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [26] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 146-480. RX PubMed=12086620; DOI=10.1016/s1097-2765(02)00550-6; RA Yang J., Cron P., Thompson V., Good V.M., Hess D., Hemmings B.A., RA Barford D.; RT "Molecular mechanism for the regulation of protein kinase B/Akt by RT hydrophobic motif phosphorylation."; RL Mol. Cell 9:1227-1240(2002). RN [27] RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 146-467 IN COMPLEX WITH RP PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER AND MANGANESE, AND RP PHOSPHORYLATION AT THR-309. RX PubMed=12434148; DOI=10.1038/nsb870; RA Yang J., Cron P., Good V.M., Thompson V., Hemmings B.A., Barford D.; RT "Crystal structure of an activated Akt/protein kinase B ternary complex RT with GSK3-peptide and AMP-PNP."; RL Nat. Struct. Biol. 9:940-944(2002). RN [28] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 143-481, ATP-BINDING, RP SUBSTRATE-BINDING, AND DISULFIDE BOND. RX PubMed=12517337; DOI=10.1016/s0969-2126(02)00937-1; RA Huang X., Begley M., Morgenstern K.A., Gu Y., Rose P., Zhao H., Zhu X.; RT "Crystal structure of an inactive Akt2 kinase domain."; RL Structure 11:21-30(2003). RN [29] RP STRUCTURE BY NMR OF 1-111. RX PubMed=14755158; DOI=10.1023/b:jnmr.0000013836.62154.c2; RA Auguin D., Barthe P., Auge-Senegas M.T., Stern M.H., Noguchi M., RA Roumestand C.; RT "Solution structure and backbone dynamics of the pleckstrin homology domain RT of the human protein kinase B (PKB/Akt). Interaction with inositol RT phosphates."; RL J. Biomol. NMR 28:137-155(2004). RN [30] RP FUNCTION. RX PubMed=31204173; DOI=10.1016/j.devcel.2019.05.022; RA Walia V., Cuenca A., Vetter M., Insinna C., Perera S., Lu Q., Ritt D.A., RA Semler E., Specht S., Stauffer J., Morrison D.K., Lorentzen E., RA Westlake C.J.; RT "Akt Regulates a Rab11-Effector Switch Required for Ciliogenesis."; RL Dev. Cell 50:229-246(2019). RN [31] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 146-467, AND INHIBITOR-BINDING. RX PubMed=17275837; DOI=10.1016/j.jmb.2007.01.004; RA Davies T.G., Verdonk M.L., Graham B., Saalau-Bethell S., Hamlett C.C., RA McHardy T., Collins I., Garrett M.D., Workman P., Woodhead S.J., Jhoti H., RA Barford D.; RT "A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB RT chimera."; RL J. Mol. Biol. 367:882-894(2007). RN [32] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 146-480, AND ACTIVITY REGULATION. RX PubMed=18800763; DOI=10.1021/jm8004527; RA Heerding D.A., Rhodes N., Leber J.D., Clark T.J., Keenan R.M., RA Lafrance L.V., Li M., Safonov I.G., Takata D.T., Venslavsky J.W., RA Yamashita D.S., Choudhry A.E., Copeland R.A., Lai Z., Schaber M.D., RA Tummino P.J., Strum S.L., Wood E.R., Duckett D.R., Eberwein D., Knick V.B., RA Lansing T.J., McConnell R.T., Zhang S., Minthorn E.A., Concha N.O., RA Warren G.L., Kumar R.; RT "Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3- RT piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol RT (GSK690693), a novel inhibitor of AKT kinase."; RL J. Med. Chem. 51:5663-5679(2008). RN [33] {ECO:0007744|PDB:3E87, ECO:0007744|PDB:3E88, ECO:0007744|PDB:3E8D} RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 146-480, AND ACTIVITY REGULATION. RX PubMed=19179070; DOI=10.1016/j.bmcl.2009.01.002; RA Rouse M.B., Seefeld M.A., Leber J.D., McNulty K.C., Sun L., Miller W.H., RA Zhang S., Minthorn E.A., Concha N.O., Choudhry A.E., Schaber M.D., RA Heerding D.A.; RT "Aminofurazans as potent inhibitors of AKT kinase."; RL Bioorg. Med. Chem. Lett. 19:1508-1511(2009). RN [34] RP VARIANT HIS-274, AND INVOLVEMENT IN T2D. RX PubMed=15166380; DOI=10.1126/science.1096706; RA George S., Rochford J.J., Wolfrum C., Gray S.L., Schinner S., Wilson J.C., RA Soos M.A., Murgatroyd P.R., Williams R.M., Acerini C.L., Dunger D.B., RA Barford D., Umpleby A.M., Wareham N.J., Davies H.A., Schafer A.J., RA Stoffel M., O'Rahilly S., Barroso I.; RT "A family with severe insulin resistance and diabetes due to a mutation in RT AKT2."; RL Science 304:1325-1328(2004). RN [35] RP VARIANTS [LARGE SCALE ANALYSIS] VAL-188 AND LYS-208. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [36] RP VARIANT HIS-274, AND INVOLVEMENT IN T2D. RX PubMed=19164855; DOI=10.1172/jci37432; RA Semple R.K., Sleigh A., Murgatroyd P.R., Adams C.A., Bluck L., Jackson S., RA Vottero A., Kanabar D., Charlton-Menys V., Durrington P., Soos M.A., RA Carpenter T.A., Lomas D.J., Cochran E.K., Gorden P., O'Rahilly S., RA Savage D.B.; RT "Postreceptor insulin resistance contributes to human dyslipidemia and RT hepatic steatosis."; RL J. Clin. Invest. 119:315-322(2009). RN [37] RP VARIANT HIHGHH LYS-17. RX PubMed=21979934; DOI=10.1126/science.1210878; RA Hussain K., Challis B., Rocha N., Payne F., Minic M., Thompson A., Daly A., RA Scott C., Harris J., Smillie B.J., Savage D.B., Ramaswami U., De Lonlay P., RA O'Rahilly S., Barroso I., Semple R.K.; RT "An activating mutation of AKT2 and human hypoglycemia."; RL Science 334:474-474(2011). CC -!- FUNCTION: AKT2 is one of 3 closely related serine/threonine-protein CC kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate CC many processes including metabolism, proliferation, cell survival, CC growth and angiogenesis. This is mediated through serine and/or CC threonine phosphorylation of a range of downstream substrates. Over 100 CC substrate candidates have been reported so far, but for most of them, CC no isoform specificity has been reported. AKT is responsible of the CC regulation of glucose uptake by mediating insulin-induced translocation CC of the SLC2A4/GLUT4 glucose transporter to the cell surface. CC Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its CC phosphatase activity preventing dephosphorylation of the insulin CC receptor and the attenuation of insulin signaling. Phosphorylation of CC TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 CC proteins, which is required for insulin-stimulated glucose transport. CC AKT regulates also the storage of glucose in the form of glycogen by CC phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in CC inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by CC AKT is also thought to be one mechanism by which cell proliferation is CC driven. AKT regulates also cell survival via the phosphorylation of CC MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' CC decreases MAP3K5 kinase activity stimulated by oxidative stress and CC thereby prevents apoptosis. AKT mediates insulin-stimulated protein CC synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby CC activating mTORC1 signaling and leading to both phosphorylation of 4E- CC BP1 and in activation of RPS6KB1. AKT is involved in the CC phosphorylation of members of the FOXO factors (Forkhead family of CC transcription factors), leading to binding of 14-3-3 proteins and CC cytoplasmic localization. In particular, FOXO1 is phosphorylated at CC 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated CC on equivalent sites. AKT has an important role in the regulation of NF- CC kappa-B-dependent gene transcription and positively regulates the CC activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). CC The phosphorylation of CREB1 induces the binding of accessory proteins CC that are necessary for the transcription of pro-survival genes such as CC BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase CC (ACLY), thereby potentially regulating ACLY activity and fatty acid CC synthesis. Activates the 3B isoform of cyclic nucleotide CC phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting CC in reduced cyclic AMP levels and inhibition of lipolysis. CC Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P- CC 5 activity. The Rho GTPase-activating protein DLC1 is another substrate CC and its phosphorylation is implicated in the regulation cell CC proliferation and cell growth. AKT plays a role as key modulator of the CC AKT-mTOR signaling pathway controlling the tempo of the process of CC newborn neurons integration during adult neurogenesis, including CC correct neuron positioning, dendritic development and synapse CC formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) CC to mediate the effects of various growth factors such as platelet- CC derived growth factor (PDGF), epidermal growth factor (EGF), insulin CC and insulin-like growth factor I (IGF-I). AKT mediates the CC antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated CC regulation of cell migration and adhesion assembly and disassembly. May CC be involved in the regulation of the placental development. Involved in CC the inhibition of ciliogenesis associated with RAB8-dependent cilia CC growth (PubMed:31204173). {ECO:0000269|PubMed:31204173}. CC -!- FUNCTION: One of the few specific substrates of AKT2 identified CC recently is PITX2. Phosphorylation of PITX2 impairs its association CC with the CCND1 mRNA-stabilizing complex thus shortening the half-life CC of CCND1. AKT2 seems also to be the principal isoform responsible of CC the regulation of glucose uptake. Phosphorylates C2CD5 on 'Ser-197' CC during insulin-stimulated adipocytes. AKT2 is also specifically CC involved in skeletal muscle differentiation, one of its substrates in CC this process being ANKRD2. Down-regulation by RNA interference reduces CC the expression of the phosphorylated form of BAD, resulting in the CC induction of caspase-dependent apoptosis. Phosphorylates CLK2 on 'Thr- CC 343'. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; CC -!- ACTIVITY REGULATION: Two specific sites, one in the kinase domain (Thr- CC 309) and the other in the C-terminal regulatory region (Ser-474), need CC to be phosphorylated for its full activation (PubMed:18800763, CC PubMed:19179070). Aminofurazans, such as 4-[2-(4-amino-2,5- CC dihydro-1,2,5-oxadiazol-3-yl)-6-{[(1S)-3-amino-1-phenylpropyl]oxy}-1- CC ethyl-1H-imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol (compound CC 32), are potent AKT2 inhibitors (PubMed:19179070). CC {ECO:0000269|PubMed:18800763, ECO:0000269|PubMed:19179070}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=358.4 uM for ATP (for purified and in vitro activated AKT2) CC {ECO:0000269|PubMed:16540465}; CC KM=3.4 uM for peptide substrate (for purified and in vitro activated CC AKT2) {ECO:0000269|PubMed:16540465}; CC KM=564 uM for ATP (for recombinant myristoylated AKT2 expressed and CC immunoprecipitated from Rat-1 cells) {ECO:0000269|PubMed:16540465}; CC KM=2.3 uM for peptide substrate (for recombinant myristoylated AKT2 CC expressed and immunoprecipitated from Rat-1 cells) CC {ECO:0000269|PubMed:16540465}; CC -!- SUBUNIT: Interacts with BTBD10 (By similarity). Interacts with KCTD20 CC (By similarity). Interacts (via PH domain) with MTCP1, TCL1A and TCL1B. CC Interacts with CLK2, PBH2 and TRAF6. Interacts (when phosphorylated) CC with CLIP3, the interaction promotes cell membrane localization CC (PubMed:19139280). Interacts with WDFY2 (via WD repeats 1-3) CC (PubMed:16792529). {ECO:0000250|UniProtKB:Q60823, CC ECO:0000269|PubMed:10983986, ECO:0000269|PubMed:12434148, CC ECO:0000269|PubMed:16792529, ECO:0000269|PubMed:17565718, CC ECO:0000269|PubMed:19139280, ECO:0000269|PubMed:19713527, CC ECO:0000269|PubMed:21737686}. CC -!- INTERACTION: CC P31751; P49841: GSK3B; NbExp=2; IntAct=EBI-296058, EBI-373586; CC P31751; P08238: HSP90AB1; NbExp=2; IntAct=EBI-296058, EBI-352572; CC P31751; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-296058, EBI-16439278; CC P31751; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-296058, EBI-79165; CC P31751; Q04864-2: REL; NbExp=3; IntAct=EBI-296058, EBI-10829018; CC P31751; O60504: SORBS3; NbExp=3; IntAct=EBI-296058, EBI-741237; CC P31751; P53804: TTC3; NbExp=5; IntAct=EBI-296058, EBI-2681313; CC P31751; P08670: VIM; NbExp=6; IntAct=EBI-296058, EBI-353844; CC P31751-1; Q15118-1: PDK1; NbExp=2; IntAct=EBI-12562336, EBI-12562315; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell membrane; Peripheral CC membrane protein. Early endosome {ECO:0000250|UniProtKB:Q60823}. CC Note=Localizes within both nucleus and cytoplasm of proliferative CC primary myoblasts and mostly within the nucleus of differentiated CC primary myoblasts. By virtue of the N-terminal PH domain, is recruited CC to sites of the plasma membrane containing increased PI(3,4,5)P3 or CC PI(3,4)P2, cell membrane targeting is also facilitared by interaction CC with CLIP3. Colocalizes with WDFY2 in early endosomes (By similarity). CC {ECO:0000250|UniProtKB:Q60823}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P31751-1; Sequence=Displayed; CC Name=2; CC IsoId=P31751-2; Sequence=VSP_056930; CC -!- TISSUE SPECIFICITY: Expressed in all cell types so far analyzed. CC -!- DOMAIN: Binding of the PH domain to phosphatidylinositol 3,4,5- CC trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase CC alpha (PIK3CA) activity results in its targeting to the plasma CC membrane. CC -!- PTM: Phosphorylation on Thr-309 and Ser-474 is required for full CC activity. {ECO:0000269|PubMed:12434148, ECO:0000269|PubMed:15890450, CC ECO:0000269|PubMed:20059950, ECO:0000269|PubMed:9512493}. CC -!- PTM: Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked CC polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT2 ubiquitination. CC When fully phosphorylated and translocated into the nucleus, undergoes CC 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its CC degradation by the proteasome. {ECO:0000269|PubMed:19713527, CC ECO:0000269|PubMed:20059950}. CC -!- PTM: O-GlcNAcylation at Thr-306 and Thr-313 inhibits activating CC phosphorylation at Thr-309 via disrupting the interaction between AKT CC and PDK1. {ECO:0000250}. CC -!- DISEASE: Note=Defects in AKT2 are a cause of susceptibility to breast CC cancer (BC). AKT2 promotes metastasis of tumor cells without affecting CC the latency of tumor development. With AKT3, also plays a pivotal role CC in the biology of glioblastoma. CC -!- DISEASE: Type 2 diabetes mellitus (T2D) [MIM:125853]: A multifactorial CC disorder of glucose homeostasis caused by a lack of sensitivity to the CC body's own insulin. Affected individuals usually have an obese body CC habitus and manifestations of a metabolic syndrome characterized by CC diabetes, insulin resistance, hypertension and hypertriglyceridemia. CC The disease results in long-term complications that affect the eyes, CC kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15166380, CC ECO:0000269|PubMed:19164855}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Hypoinsulinemic hypoglycemia with hemihypertrophy (HIHGHH) CC [MIM:240900]: A disorder characterized by hypoglycemia, low insulin CC levels, low serum levels of ketone bodies and branched-chain amino CC acids, left-sided hemihypertrophy, neonatal macrosomia, reduced CC consciousness and hypoglycemic seizures. {ECO:0000269|PubMed:21979934}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr CC protein kinase family. RAC subfamily. {ECO:0000305}. CC -!- CAUTION: In light of strong homologies in the primary amino acid CC sequence, the 3 AKT kinases were long surmised to play redundant and CC overlapping roles. More recent studies has brought into question the CC redundancy within AKT kinase isoforms and instead pointed to isoform CC specific functions in different cellular events and diseases. AKT1 is CC more specifically involved in cellular survival pathways, by inhibiting CC apoptotic processes; whereas AKT2 is more specific for the insulin CC receptor signaling pathway. Moreover, while AKT1 and AKT2 are often CC implicated in many aspects of cellular transformation, the 2 isoforms CC act in a complementary opposing manner. The role of AKT3 is less clear, CC though it appears to be predominantly expressed in brain. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/517/AKT2"; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/akt2/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M77198; AAA36585.1; -; mRNA. DR EMBL; M95936; AAA58364.1; -; mRNA. DR EMBL; AK314619; BAG37185.1; -; mRNA. DR EMBL; AC118344; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC032709; AAH32709.1; -; mRNA. DR EMBL; BC120995; AAI20996.1; -; mRNA. DR EMBL; BC120994; AAI20995.1; -; mRNA. DR EMBL; AY708392; AAT97984.1; -; Genomic_DNA. DR CCDS; CCDS12552.1; -. [P31751-1] DR CCDS; CCDS82350.1; -. [P31751-2] DR PIR; A46288; A46288. DR RefSeq; NP_001317440.1; NM_001330511.1. [P31751-2] DR RefSeq; NP_001617.1; NM_001626.5. [P31751-1] DR RefSeq; XP_011524916.1; XM_011526614.1. DR RefSeq; XP_011524917.1; XM_011526615.1. DR RefSeq; XP_011524918.1; XM_011526616.1. DR RefSeq; XP_011524920.1; XM_011526618.1. DR RefSeq; XP_011524921.1; XM_011526619.1. DR RefSeq; XP_011524922.1; XM_011526620.1. DR RefSeq; XP_016881959.1; XM_017026470.1. DR PDB; 1GZK; X-ray; 2.30 A; A=146-460. DR PDB; 1GZN; X-ray; 2.50 A; A=146-480. DR PDB; 1GZO; X-ray; 2.75 A; A=146-460. DR PDB; 1MRV; X-ray; 2.80 A; A=143-481. DR PDB; 1MRY; X-ray; 2.80 A; A=143-481. DR PDB; 1O6K; X-ray; 1.70 A; A=146-481. DR PDB; 1O6L; X-ray; 1.60 A; A=146-467. DR PDB; 1P6S; NMR; -; A=1-111. DR PDB; 2JDO; X-ray; 1.80 A; A=146-467. DR PDB; 2JDR; X-ray; 2.30 A; A=146-467. DR PDB; 2UW9; X-ray; 2.10 A; A=146-467. DR PDB; 2X39; X-ray; 1.93 A; A=146-467. DR PDB; 2XH5; X-ray; 2.72 A; A=146-479. DR PDB; 3D0E; X-ray; 2.00 A; A/B=146-480. DR PDB; 3E87; X-ray; 2.30 A; A/B=146-480. DR PDB; 3E88; X-ray; 2.50 A; A/B=146-480. DR PDB; 3E8D; X-ray; 2.70 A; A/B=146-480. DR PDB; 8Q61; X-ray; 2.32 A; A=1-481. DR PDBsum; 1GZK; -. DR PDBsum; 1GZN; -. DR PDBsum; 1GZO; -. DR PDBsum; 1MRV; -. DR PDBsum; 1MRY; -. DR PDBsum; 1O6K; -. DR PDBsum; 1O6L; -. DR PDBsum; 1P6S; -. DR PDBsum; 2JDO; -. DR PDBsum; 2JDR; -. DR PDBsum; 2UW9; -. DR PDBsum; 2X39; -. DR PDBsum; 2XH5; -. DR PDBsum; 3D0E; -. DR PDBsum; 3E87; -. DR PDBsum; 3E88; -. DR PDBsum; 3E8D; -. DR PDBsum; 8Q61; -. DR AlphaFoldDB; P31751; -. DR BMRB; P31751; -. DR SMR; P31751; -. DR BioGRID; 106711; 129. DR CORUM; P31751; -. DR DIP; DIP-32583N; -. DR ELM; P31751; -. DR IntAct; P31751; 51. DR MINT; P31751; -. DR STRING; 9606.ENSP00000375892; -. DR BindingDB; P31751; -. DR ChEMBL; CHEMBL2431; -. DR DrugBank; DB08073; (2S)-1-(1H-INDOL-3-YL)-3-{[5-(3-METHYL-1H-INDAZOL-5-YL)PYRIDIN-3-YL]OXY}PROPAN-2-AMINE. DR DrugBank; DB07859; 4-(4-CHLOROPHENYL)-4-[4-(1H-PYRAZOL-4-YL)PHENYL]PIPERIDINE. DR DrugBank; DB07947; ISOQUINOLINE-5-SULFONIC ACID (2-(2-(4-CHLOROBENZYLOXY)ETHYLAMINO)ETHYL)AMIDE. DR DrugBank; DB07812; N-[(1S)-2-amino-1-phenylethyl]-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide. DR DrugCentral; P31751; -. DR GuidetoPHARMACOLOGY; 1480; -. DR GlyCosmos; P31751; 4 sites, No reported glycans. DR GlyGen; P31751; 5 sites, 1 O-linked glycan (1 site). DR iPTMnet; P31751; -. DR PhosphoSitePlus; P31751; -. DR BioMuta; AKT2; -. DR DMDM; 1170703; -. DR CPTAC; CPTAC-2822; -. DR CPTAC; CPTAC-3117; -. DR CPTAC; CPTAC-3119; -. DR CPTAC; CPTAC-3159; -. DR CPTAC; CPTAC-3160; -. DR CPTAC; CPTAC-3161; -. DR CPTAC; CPTAC-5757; -. DR CPTAC; CPTAC-5801; -. DR CPTAC; CPTAC-5802; -. DR CPTAC; CPTAC-5803; -. DR CPTAC; CPTAC-5804; -. DR CPTAC; CPTAC-788; -. DR CPTAC; CPTAC-789; -. DR CPTAC; non-CPTAC-5334; -. DR CPTAC; non-CPTAC-5335; -. DR CPTAC; non-CPTAC-5336; -. DR CPTAC; non-CPTAC-5338; -. DR CPTAC; non-CPTAC-5339; -. DR CPTAC; non-CPTAC-5529; -. DR CPTAC; non-CPTAC-5717; -. DR CPTAC; non-CPTAC-5718; -. DR EPD; P31751; -. DR jPOST; P31751; -. DR MassIVE; P31751; -. DR MaxQB; P31751; -. DR PaxDb; 9606-ENSP00000375892; -. DR PeptideAtlas; P31751; -. DR ProteomicsDB; 54801; -. [P31751-1] DR ProteomicsDB; 58804; -. DR Pumba; P31751; -. DR Antibodypedia; 3775; 1866 antibodies from 50 providers. DR CPTC; P31751; 6 antibodies. DR DNASU; 208; -. DR Ensembl; ENST00000311278.10; ENSP00000309428.6; ENSG00000105221.18. [P31751-2] DR Ensembl; ENST00000392038.7; ENSP00000375892.2; ENSG00000105221.18. [P31751-1] DR Ensembl; ENST00000424901.5; ENSP00000399532.2; ENSG00000105221.18. [P31751-2] DR GeneID; 208; -. DR KEGG; hsa:208; -. DR MANE-Select; ENST00000392038.7; ENSP00000375892.2; NM_001626.6; NP_001617.1. DR UCSC; uc002onf.3; human. [P31751-1] DR AGR; HGNC:392; -. DR CTD; 208; -. DR DisGeNET; 208; -. DR GeneCards; AKT2; -. DR HGNC; HGNC:392; AKT2. DR HPA; ENSG00000105221; Low tissue specificity. DR MalaCards; AKT2; -. DR MIM; 125853; phenotype. DR MIM; 164731; gene. DR MIM; 240900; phenotype. DR neXtProt; NX_P31751; -. DR OpenTargets; ENSG00000105221; -. DR Orphanet; 79085; AKT2-related familial partial lipodystrophy. DR Orphanet; 293964; Hypoinsulinemic hypoglycemia and body hemihypertrophy. DR PharmGKB; PA24685; -. DR VEuPathDB; HostDB:ENSG00000105221; -. DR eggNOG; KOG0690; Eukaryota. DR GeneTree; ENSGT00940000157189; -. DR InParanoid; P31751; -. DR OrthoDB; 3028764at2759; -. DR PhylomeDB; P31751; -. DR TreeFam; TF102004; -. DR BRENDA; 2.7.11.1; 2681. DR PathwayCommons; P31751; -. DR Reactome; R-HSA-111447; Activation of BAD and translocation to mitochondria. DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling. DR Reactome; R-HSA-1358803; Downregulation of ERBB2:ERBB3 signaling. DR Reactome; R-HSA-1445148; Translocation of SLC2A4 (GLUT4) to the plasma membrane. DR Reactome; R-HSA-165158; Activation of AKT2. DR Reactome; R-HSA-165160; PDE3B signalling. DR Reactome; R-HSA-165181; Inhibition of TSC complex formation by PKB. DR Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol. DR Reactome; R-HSA-198693; AKT phosphorylates targets in the nucleus. DR Reactome; R-HSA-199418; Negative regulation of the PI3K/AKT network. DR Reactome; R-HSA-211163; AKT-mediated inactivation of FOXO1A. DR Reactome; R-HSA-3769402; Deactivation of the beta-catenin transactivating complex. DR Reactome; R-HSA-389357; CD28 dependent PI3K/Akt signaling. DR Reactome; R-HSA-389513; CTLA4 inhibitory signaling. DR Reactome; R-HSA-392451; G beta:gamma signalling through PI3Kgamma. DR Reactome; R-HSA-5218920; VEGFR2 mediated vascular permeability. DR Reactome; R-HSA-5628897; TP53 Regulates Metabolic Genes. DR Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer. DR Reactome; R-HSA-6804757; Regulation of TP53 Degradation. DR Reactome; R-HSA-6804758; Regulation of TP53 Activity through Acetylation. DR Reactome; R-HSA-6804759; Regulation of TP53 Activity through Association with Co-factors. DR Reactome; R-HSA-69202; Cyclin E associated events during G1/S transition. DR Reactome; R-HSA-69656; Cyclin A:Cdk2-associated events at S phase entry. DR Reactome; R-HSA-8876198; RAB GEFs exchange GTP for GDP on RABs. DR Reactome; R-HSA-8941332; RUNX2 regulates genes involved in cell migration. DR Reactome; R-HSA-8948751; Regulation of PTEN stability and activity. DR Reactome; R-HSA-9607240; FLT3 Signaling. DR Reactome; R-HSA-9614399; Regulation of localization of FOXO transcription factors. DR Reactome; R-HSA-9634638; Estrogen-dependent nuclear events downstream of ESR-membrane signaling. DR Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway. DR Reactome; R-HSA-9755779; SARS-CoV-2 targets host intracellular signalling and regulatory pathways. DR SABIO-RK; P31751; -. DR SignaLink; P31751; -. DR SIGNOR; P31751; -. DR BioGRID-ORCS; 208; 39 hits in 1204 CRISPR screens. DR ChiTaRS; AKT2; human. DR EvolutionaryTrace; P31751; -. DR GeneWiki; AKT2; -. DR GenomeRNAi; 208; -. DR Pharos; P31751; Tchem. DR PRO; PR:P31751; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; P31751; Protein. DR Bgee; ENSG00000105221; Expressed in right uterine tube and 178 other cell types or tissues. DR ExpressionAtlas; P31751; baseline and differential. DR GO; GO:0005938; C:cell cortex; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0032587; C:ruffle membrane; ISS:UniProtKB. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0140677; F:molecular function activator activity; EXP:DisProt. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0008643; P:carbohydrate transport; IEA:UniProtKB-KW. DR GO; GO:0071486; P:cellular response to high light intensity; IEA:Ensembl. DR GO; GO:0032869; P:cellular response to insulin stimulus; IMP:BHF-UCL. DR GO; GO:0045444; P:fat cell differentiation; TAS:UniProtKB. DR GO; GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW. DR GO; GO:0005978; P:glycogen biosynthetic process; IEA:UniProtKB-KW. DR GO; GO:0008286; P:insulin receptor signaling pathway; IMP:BHF-UCL. DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central. DR GO; GO:0060644; P:mammary gland epithelial cell differentiation; TAS:UniProtKB. DR GO; GO:0010748; P:negative regulation of long-chain fatty acid import across plasma membrane; IMP:BHF-UCL. DR GO; GO:0032287; P:peripheral nervous system myelin maintenance; IEA:Ensembl. DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:0030335; P:positive regulation of cell migration; IDA:BHF-UCL. DR GO; GO:2000147; P:positive regulation of cell motility; IMP:BHF-UCL. DR GO; GO:0032000; P:positive regulation of fatty acid beta-oxidation; IMP:BHF-UCL. DR GO; GO:0046326; P:positive regulation of glucose import; IMP:BHF-UCL. DR GO; GO:0010907; P:positive regulation of glucose metabolic process; IMP:BHF-UCL. DR GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; IMP:BHF-UCL. DR GO; GO:0090314; P:positive regulation of protein targeting to membrane; ISS:UniProtKB. DR GO; GO:0072659; P:protein localization to plasma membrane; IEA:Ensembl. DR GO; GO:0036211; P:protein modification process; TAS:ProtInc. DR GO; GO:0051726; P:regulation of cell cycle; TAS:UniProtKB. DR GO; GO:0030334; P:regulation of cell migration; TAS:UniProtKB. DR GO; GO:0006417; P:regulation of translation; IEA:UniProtKB-KW. DR GO; GO:0097473; P:retinal rod cell apoptotic process; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; TAS:UniProtKB. DR CDD; cd01241; PH_PKB; 1. DR CDD; cd05595; STKc_PKB_beta; 1. DR DisProt; DP00304; -. DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR IDEAL; IID00037; -. DR InterPro; IPR000961; AGC-kinase_C. DR InterPro; IPR034677; Akt2. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR011993; PH-like_dom_sf. DR InterPro; IPR001849; PH_domain. DR InterPro; IPR039026; PH_PKB. DR InterPro; IPR017892; Pkinase_C. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR24351:SF192; PROTEIN KINASE C; 1. DR PANTHER; PTHR24351; RIBOSOMAL PROTEIN S6 KINASE; 1. DR Pfam; PF00169; PH; 1. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF00433; Pkinase_C; 1. DR SMART; SM00233; PH; 1. DR SMART; SM00133; S_TK_X; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF50729; PH domain-like; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS51285; AGC_KINASE_CTER; 1. DR PROSITE; PS50003; PH_DOMAIN; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; P31751; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Apoptosis; ATP-binding; KW Carbohydrate metabolism; Cell membrane; Cytoplasm; Developmental protein; KW Diabetes mellitus; Disease variant; Disulfide bond; Endosome; KW Glucose metabolism; Glycogen biosynthesis; Glycogen metabolism; KW Glycoprotein; Kinase; Manganese; Membrane; Metal-binding; KW Nucleotide-binding; Nucleus; Phosphoprotein; Proto-oncogene; KW Reference proteome; Serine/threonine-protein kinase; Sugar transport; KW Transferase; Translation regulation; Transport; Ubl conjugation. FT CHAIN 1..481 FT /note="RAC-beta serine/threonine-protein kinase" FT /id="PRO_0000085608" FT DOMAIN 5..108 FT /note="PH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145" FT DOMAIN 152..409 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 410..481 FT /note="AGC-kinase C-terminal" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618" FT ACT_SITE 275 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 158..166 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 181 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 280 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /evidence="ECO:0000269|PubMed:12434148" FT BINDING 293 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /evidence="ECO:0000269|PubMed:12434148" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:22223895" FT MOD_RES 34 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 126 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 309 FT /note="Phosphothreonine; by PDPK1" FT /evidence="ECO:0000269|PubMed:12434148, FT ECO:0000269|PubMed:15890450, ECO:0000269|PubMed:20059950, FT ECO:0000269|PubMed:9512493" FT MOD_RES 447 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 451 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:24275569" FT MOD_RES 474 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:15890450, FT ECO:0000269|PubMed:20059950, ECO:0007744|PubMed:19690332" FT MOD_RES 478 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT CARBOHYD 128 FT /note="O-linked (GlcNAc) serine" FT /evidence="ECO:0000250" FT CARBOHYD 131 FT /note="O-linked (GlcNAc) serine" FT /evidence="ECO:0000250" FT CARBOHYD 306 FT /note="O-linked (GlcNAc) threonine" FT /evidence="ECO:0000250" FT CARBOHYD 313 FT /note="O-linked (GlcNAc) threonine" FT /evidence="ECO:0000250" FT DISULFID 60..77 FT /evidence="ECO:0000250" FT DISULFID 297..311 FT /evidence="ECO:0000269|PubMed:12517337" FT VAR_SEQ 278..320 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_056930" FT VARIANT 17 FT /note="E -> K (in HIHGHH; exhibits plasma membrane FT localization in serum-starved cells and produced FT inappropriate tonic nuclear exclusion of FOXO1 in FT preadipocytes; dbSNP:rs387906659)" FT /evidence="ECO:0000269|PubMed:21979934" FT /id="VAR_067309" FT VARIANT 188 FT /note="I -> V (in dbSNP:rs55859611)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040356" FT VARIANT 208 FT /note="R -> K (in dbSNP:rs35817154)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040357" FT VARIANT 274 FT /note="R -> H (risk factor for T2D; typical metabolic FT dyslipidemia with elevated fastin triglyceride, high VLDL FT triglyceride/cholesterol ratios, low HDL cholesterol levels FT and high small dense LDL levels; de novo lipogenesis and FT liver fat are also significantly elevated; FT dbSNP:rs121434593)" FT /evidence="ECO:0000269|PubMed:15166380, FT ECO:0000269|PubMed:19164855" FT /id="VAR_067310" FT MUTAGEN 309 FT /note="T->A: Impairs interaction with TTC3; when associated FT with A-474." FT /evidence="ECO:0000269|PubMed:15890450, FT ECO:0000269|PubMed:20059950" FT MUTAGEN 309 FT /note="T->E: Constitutively active; when associated with FT D-474." FT /evidence="ECO:0000269|PubMed:15890450, FT ECO:0000269|PubMed:20059950" FT MUTAGEN 474 FT /note="S->A: Impairs interaction with TTC3; when associated FT with A-309." FT /evidence="ECO:0000269|PubMed:15890450, FT ECO:0000269|PubMed:20059950" FT MUTAGEN 474 FT /note="S->D: Constitutively active; when associated with FT E-309." FT /evidence="ECO:0000269|PubMed:15890450, FT ECO:0000269|PubMed:20059950" FT CONFLICT 478..481 FT /note="SIRE -> FREEKDLLMSLFVSLILFSDFSSLKSHSFSSNFILLSFSSLKK FT (in Ref. 1; AAA36585)" FT /evidence="ECO:0000305" FT STRAND 6..15 FT /evidence="ECO:0007829|PDB:1P6S" FT STRAND 17..20 FT /evidence="ECO:0007829|PDB:1P6S" FT STRAND 22..30 FT /evidence="ECO:0007829|PDB:1P6S" FT TURN 31..33 FT /evidence="ECO:0007829|PDB:1P6S" FT STRAND 34..40 FT /evidence="ECO:0007829|PDB:1P6S" FT STRAND 45..47 FT /evidence="ECO:0007829|PDB:1P6S" FT STRAND 52..56 FT /evidence="ECO:0007829|PDB:1P6S" FT STRAND 58..60 FT /evidence="ECO:0007829|PDB:1P6S" FT STRAND 62..65 FT /evidence="ECO:0007829|PDB:1P6S" FT STRAND 67..75 FT /evidence="ECO:0007829|PDB:1P6S" FT STRAND 86..92 FT /evidence="ECO:0007829|PDB:1P6S" FT HELIX 93..110 FT /evidence="ECO:0007829|PDB:1P6S" FT HELIX 149..151 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 152..160 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 162..171 FT /evidence="ECO:0007829|PDB:1O6L" FT TURN 172..174 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 177..184 FT /evidence="ECO:0007829|PDB:1O6L" FT HELIX 185..190 FT /evidence="ECO:0007829|PDB:1O6L" FT HELIX 194..205 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 215..220 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 222..230 FT /evidence="ECO:0007829|PDB:1O6L" FT HELIX 237..244 FT /evidence="ECO:0007829|PDB:1O6L" FT HELIX 249..268 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 280..283 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 289..291 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 298..300 FT /evidence="ECO:0007829|PDB:2UW9" FT STRAND 310..312 FT /evidence="ECO:0007829|PDB:2JDO" FT HELIX 314..316 FT /evidence="ECO:0007829|PDB:1O6L" FT HELIX 319..322 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 323..325 FT /evidence="ECO:0007829|PDB:1O6L" FT HELIX 331..345 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 351..353 FT /evidence="ECO:0007829|PDB:1GZK" FT HELIX 355..364 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 371..373 FT /evidence="ECO:0007829|PDB:1GZN" FT HELIX 375..384 FT /evidence="ECO:0007829|PDB:1O6L" FT TURN 389..391 FT /evidence="ECO:0007829|PDB:1O6L" FT TURN 393..395 FT /evidence="ECO:0007829|PDB:2X39" FT TURN 397..399 FT /evidence="ECO:0007829|PDB:1O6L" FT HELIX 400..404 FT /evidence="ECO:0007829|PDB:1O6L" FT HELIX 407..409 FT /evidence="ECO:0007829|PDB:1O6L" FT HELIX 414..418 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 431..434 FT /evidence="ECO:0007829|PDB:2JDR" FT STRAND 437..439 FT /evidence="ECO:0007829|PDB:1GZO" FT HELIX 441..444 FT /evidence="ECO:0007829|PDB:1O6L" FT TURN 470..472 FT /evidence="ECO:0007829|PDB:1O6L" FT STRAND 474..476 FT /evidence="ECO:0007829|PDB:3D0E" FT TURN 477..479 FT /evidence="ECO:0007829|PDB:3D0E" SQ SEQUENCE 481 AA; 55769 MW; B18C87A7246BFB24 CRC64; MNEVSVIKEG WLHKRGEYIK TWRPRYFLLK SDGSFIGYKE RPEAPDQTLP PLNNFSVAEC QLMKTERPRP NTFVIRCLQW TTVIERTFHV DSPDEREEWM RAIQMVANSL KQRAPGEDPM DYKCGSPSDS STTEEMEVAV SKARAKVTMN DFDYLKLLGK GTFGKVILVR EKATGRYYAM KILRKEVIIA KDEVAHTVTE SRVLQNTRHP FLTALKYAFQ THDRLCFVME YANGGELFFH LSRERVFTEE RARFYGAEIV SALEYLHSRD VVYRDIKLEN LMLDKDGHIK ITDFGLCKEG ISDGATMKTF CGTPEYLAPE VLEDNDYGRA VDWWGLGVVM YEMMCGRLPF YNQDHERLFE LILMEEIRFP RTLSPEAKSL LAGLLKKDPK QRLGGGPSDA KEVMEHRFFL SINWQDVVQK KLLPPFKPQV TSEVDTRYFD DEFTAQSITI TPPDRYDSLG LLELDQRTHF PQFSYSASIR E //