AKT2_HUMAN
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 03-AUG-2022, entry version 228.
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 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 [31]
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 [32] {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 [33]
RP VARIANT NIDDM HIS-274.
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 [34]
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 [35]
RP ASSOCIATION OF VARIANT NIDDM HIS-274 WITH TYPICAL METABOLIC DYSLIPIDEMIA.
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 [36]
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.
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-dihydro-
CC 1,2,5-oxadiazol-3-yl)-6-{[(1S)-3-amino-1-phenylpropyl]oxy}-1-ethyl-1H-
CC imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol (compound 32), are
CC potent AKT2 inhibitors (PubMed:19179070). {ECO:0000269|PubMed:18800763,
CC 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: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]:
CC A multifactorial disorder of glucose homeostasis caused by a lack of
CC sensitivity to the body's own insulin. Affected individuals usually
CC have an obese body habitus and manifestations of a metabolic syndrome
CC characterized by diabetes, insulin resistance, hypertension and
CC hypertriglyceridemia. The disease results in long-term complications
CC that affect the eyes, kidneys, nerves, and blood vessels.
CC {ECO:0000269|PubMed:15166380, ECO:0000269|PubMed:19164855}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC 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="http://atlasgeneticsoncology.org/Genes/AKT2ID517ch19q13.html";
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. [P31751-1]
DR RefSeq; XP_011524917.1; XM_011526615.1. [P31751-1]
DR RefSeq; XP_011524918.1; XM_011526616.1. [P31751-1]
DR RefSeq; XP_011524920.1; XM_011526618.1. [P31751-1]
DR RefSeq; XP_011524921.1; XM_011526619.1. [P31751-1]
DR RefSeq; XP_011524922.1; XM_011526620.1. [P31751-1]
DR RefSeq; XP_016881959.1; XM_017026470.1. [P31751-1]
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 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 AlphaFoldDB; P31751; -.
DR BMRB; P31751; -.
DR SMR; P31751; -.
DR BioGRID; 106711; 99.
DR CORUM; P31751; -.
DR DIP; DIP-32583N; -.
DR ELM; P31751; -.
DR IntAct; P31751; 46.
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 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-788; -.
DR CPTAC; CPTAC-789; -.
DR EPD; P31751; -.
DR jPOST; P31751; -.
DR MassIVE; P31751; -.
DR MaxQB; P31751; -.
DR PaxDb; P31751; -.
DR PeptideAtlas; P31751; -.
DR PRIDE; P31751; -.
DR ProteomicsDB; 54801; -. [P31751-1]
DR ProteomicsDB; 58804; -.
DR Antibodypedia; 3775; 1690 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 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; 442523at2759; -.
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; 35 hits in 1116 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 176 other tissues.
DR ExpressionAtlas; P31751; baseline and differential.
DR Genevisible; P31751; HS.
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:0032991; C:protein-containing complex; IDA: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:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0090630; P:activation of GTPase activity; IEA:Ensembl.
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:0065002; P:intracellular protein transmembrane transport; ISS:UniProtKB.
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:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0010748; P:negative regulation of long-chain fatty acid import across plasma membrane; IMP:BHF-UCL.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR GO; GO:0032287; P:peripheral nervous system myelin maintenance; IEA:Ensembl.
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:0008284; P:positive regulation of cell population proliferation; IMP:UniProtKB.
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:0010918; P:positive regulation of mitochondrial membrane potential; IMP:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0090314; P:positive regulation of protein targeting to membrane; ISS:UniProtKB.
DR GO; GO:0031340; P:positive regulation of vesicle fusion; 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; -; 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 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; SSF56112; SSF56112; 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.
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 (in NIDDM; associated with 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 in this subject;
FT dbSNP:rs121434593)"
FT /evidence="ECO:0000269|PubMed:15166380"
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 D-
FT 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 E-
FT 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
