UniProt Accession

 AKT2_HUMAN; P31751; B2RBD8; Q0VAN1; Q68GC0 

Genbank Protein ID

 M77198; M95936; AK314619; BC120994; AY708392 

Genbank Nucleotide ID

 AAA36585.1; AAA58364.1; BAG37185.1; AAI20995.1; AAT97984.1 

Protein Name

 RAC-beta serine/threonine-protein kinase 

Protein Synonyms/Alias

 Protein kinase Akt-2; Protein kinase B beta; PKB beta; RAC-PK-beta 

Gene Name

 AKT2 

Gene Synonyms/Alias

  

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
14	IKEGWLHKRGEYIKT	ubiquitination	[1]
30	RPRYFLLKSDGSFIG	ubiquitination	[2, 3]
111	QMVANSLKQRAPGED	ubiquitination	[1]
142	EMEVAVSKARAKVTM	ubiquitination	[1]
146	AVSKARAKVTMNDFD	ubiquitination	[1]
156	MNDFDYLKLLGKGTF	ubiquitination	[1]
160	DYLKLLGKGTFGKVI	ubiquitination	[1]
277	DVVYRDIKLENLMLD	ubiquitination	[4]
298	ITDFGLCKEGISDGA	ubiquitination	[1]
378	RTLSPEAKSLLAGLL	ubiquitination	[1, 2, 3]
401	GGGPSDAKEVMEHRF	ubiquitination	[1]
427	KKLLPPFKPQVTSEV	ubiquitination	[1]

Reference

 [1] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [2] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [3] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [4] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983] 

Functional Description

 AKT2 is one of 3 closely related serine/threonine- protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)- response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. 

Sequence Annotation

 DOMAIN 5 108 PH.
 DOMAIN 152 409 Protein kinase.
 DOMAIN 410 481 AGC-kinase C-terminal.
 NP_BIND 158 166 ATP (By similarity).
 REGION 230 232 Inhibitor binding.
 REGION 277 279 Inhibitor binding.
 REGION 292 293 Inhibitor binding.
 ACT_SITE 275 275 Proton acceptor (By similarity).
 BINDING 181 181 ATP (By similarity).
 BINDING 181 181 Inhibitor.
 BINDING 200 200 Inhibitor.
 BINDING 232 232 Inhibitor; via amide nitrogen.
 BINDING 236 236 Inhibitor.
 BINDING 279 279 Inhibitor; via carbonyl oxygen.
 BINDING 280 280 Manganese.
 BINDING 293 293 Inhibitor.
 BINDING 293 293 Manganese.
 BINDING 294 294 Inhibitor; via amide nitrogen.
 MOD_RES 126 126 Phosphoserine.
 MOD_RES 309 309 Phosphothreonine; by PDPK1.
 MOD_RES 447 447 Phosphoserine.
 MOD_RES 451 451 Phosphothreonine.
 MOD_RES 474 474 Phosphoserine.
 MOD_RES 478 478 Phosphoserine.
 CARBOHYD 128 128 O-linked (GlcNAc...) (By similarity).
 CARBOHYD 131 131 O-linked (GlcNAc...) (By similarity).
 CARBOHYD 306 306 O-linked (GlcNAc...) (By similarity).
 CARBOHYD 313 313 O-linked (GlcNAc...) (By similarity).
 DISULFID 60 77 By similarity.
 DISULFID 297 311  

Keyword

 3D-structure; Apoptosis; ATP-binding; Carbohydrate metabolism; Cell membrane; Complete proteome; Cytoplasm; Developmental protein; Diabetes mellitus; Disease mutation; Disulfide bond; Glucose metabolism; Glycogen biosynthesis; Glycogen metabolism; Glycoprotein; Kinase; Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Proto-oncogene; Reference proteome; Serine/threonine-protein kinase; Sugar transport; Transferase; Translation regulation; Transport; Ubl conjugation. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 481 AA 

Protein Sequence

Gene Ontology

 GO:0005938; C:cell cortex; ISS:UniProtKB.
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0030027; C:lamellipodium; IEA:Compara.
 GO:0005634; C:nucleus; IDA:UniProtKB.
 GO:0032587; C:ruffle membrane; ISS:UniProtKB.
 GO:0005524; F:ATP binding; IDA:UniProtKB.
 GO:0005543; F:phospholipid binding; IEA:InterPro.
 GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
 GO:0032859; P:activation of Ral GTPase activity; IEA:Compara.
 GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
 GO:0008643; P:carbohydrate transport; IEA:UniProtKB-KW.
 GO:0016044; P:cellular membrane organization; TAS:Reactome.
 GO:0045444; P:fat cell differentiation; TAS:UniProtKB.
 GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW.
 GO:0005978; P:glycogen biosynthetic process; IEA:UniProtKB-KW.
 GO:0008286; P:insulin receptor signaling pathway; TAS:UniProtKB.
 GO:0065002; P:intracellular protein transmembrane transport; ISS:UniProtKB.
 GO:0060644; P:mammary gland epithelial cell differentiation; TAS:UniProtKB.
 GO:0010748; P:negative regulation of plasma membrane long-chain fatty acid transport; IMP:BHF-UCL.
 GO:0032287; P:peripheral nervous system myelin maintenance; IEA:Compara.
 GO:2000147; P:positive regulation of cell motility; IMP:BHF-UCL.
 GO:0032000; P:positive regulation of fatty acid beta-oxidation; IMP:BHF-UCL.
 GO:0046326; P:positive regulation of glucose import; IMP:BHF-UCL.
 GO:2001275; P:positive regulation of glucose import in response to insulin stimulus; IEA:Compara.
 GO:0045725; P:positive regulation of glycogen biosynthetic process; IMP:BHF-UCL.
 GO:0001934; P:positive regulation of protein phosphorylation; ISS:UniProtKB.
 GO:0090314; P:positive regulation of protein targeting to membrane; ISS:UniProtKB.
 GO:0031340; P:positive regulation of vesicle fusion; ISS:UniProtKB.
 GO:0072659; P:protein localization to plasma membrane; IEA:Compara.
 GO:0071156; P:regulation of cell cycle arrest; TAS:UniProtKB.
 GO:0030334; P:regulation of cell migration; TAS:UniProtKB.
 GO:0046328; P:regulation of JNK cascade; IEA:Compara.
 GO:0006417; P:regulation of translation; IEA:UniProtKB-KW. 

Interpro

 IPR000961; AGC-kinase_C.
 IPR011009; Kinase-like_dom.
 IPR011993; PH_like_dom.
 IPR017892; Pkinase_C.
 IPR001849; Pleckstrin_homology.
 IPR000719; Prot_kinase_cat_dom.
 IPR017441; Protein_kinase_ATP_BS.
 IPR002290; Ser/Thr_dual-sp_kinase_dom.
 IPR008271; Ser/Thr_kinase_AS. 

Pfam

 PF00169; PH
 PF00069; Pkinase
 PF00433; Pkinase_C 

SMART

 SM00233; PH
 SM00133; S_TK_X
 SM00220; S_TKc 

PROSITE

 PS51285; AGC_KINASE_CTER
 PS50003; PH_DOMAIN
 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00108; PROTEIN_KINASE_ST 

PRINTS