ID:AKT2_HUMAN DESCRIPTION: RecName: Full=RAC-beta serine/threonine-protein kinase; EC=2.7.11.1; AltName: Full=Protein kinase Akt-2; AltName: Full=Protein kinase B beta; Short=PKB beta; AltName: Full=RAC-PK-beta; FUNCTION: 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. FUNCTION: One of the few specific substrates of AKT2 identified recently is PITX2. Phosphorylation of PITX2 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1. AKT2 seems also to be the principal isoform responsible of the regulation of glucose uptake. AKT2 is also specifically involved in skeletal muscle differentiation. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis. Phosphorylates CLK2 on 'Thr-343'. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Two specific sites, one in the kinase domain (Thr-309) and the other in the C-terminal regulatory region (Ser- 474), need to be phosphorylated for its full activation. Aminofurazans are potent AKT2 inhibitors. BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=358.4 uM for ATP (for purified and in vitro activated AKT2); KM=3.4 uM for peptide substrate (for purified and in vitro activated AKT2); KM=564 uM for ATP (for recombinant myristoylated AKT2 expressed and immunoprecipitated from Rat-1 cells); KM=2.3 uM for peptide substrate (for recombinant myristoylated AKT2 expressed and immunoprecipitated from Rat-1 cells); SUBUNIT: Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with CLK2, PBH2 and TRAF6. INTERACTION: P49841:GSK3B; NbExp=2; IntAct=EBI-296058, EBI-373586; P08670:VIM; NbExp=6; IntAct=EBI-296058, EBI-353844; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell membrane; Peripheral membrane protein. Note=Localizes within both nucleus and cytoplasm of proliferative primary myoblasts and mostly within the nucleus of differentiated primary myoblasts. By virtue of the N-terminal PH domain, is recruited to sites of the plasma membrane containing increased PI(3,4,5)P3 or PI(3,4)P2. TISSUE SPECIFICITY: Expressed in all cell types so far analyzed. DOMAIN: Binding of the PH domain to phosphatidylinositol 3,4,5- trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3- kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. PTM: Phosphorylation on Thr-309 and Ser-474 is required for full activity. PTM: Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT2 ubiquitination. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. PTM: O-GlcNAcylation at Thr-306 and Thr-313 inhibits activating phosphorylation at Thr-309 via disrupting the interaction between AKT and PDK1 (By similarity). DISEASE: Note=Defects in AKT2 are a cause of susceptibility to breast cancer (BC). AKT2 promotes metastasis of tumor cells without affecting the latency of tumor development. With AKT3, plays also a pivotal role in the biology of glioblastoma. DISEASE: Defects in AKT2 are a cause of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853]; also known as diabetes mellitus type 2 or maturity-onset diabetes. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance. DISEASE: Defects in AKT2 are a cause of hypoinsulinemic hypoglycemia with hemihypertrophy (HIHGHH) [MIM:240900]. HIHGHH is a disorder characterized by hypoglycemia, low insulin levels, low serum levels of ketone bodies and branched-chain amino acids, left-sided hemihypertrophy, neonatal macrosomia, reduced consciousness and hypoglycemic seizures. SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily. SIMILARITY: Contains 1 AGC-kinase C-terminal domain. SIMILARITY: Contains 1 PH domain. SIMILARITY: Contains 1 protein kinase domain. CAUTION: In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/AKT2ID517ch19q13.html"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/akt2/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P31751
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001934 positive regulation of protein phosphorylation GO:0005975 carbohydrate metabolic process GO:0005977 glycogen metabolic process GO:0005978 glycogen biosynthetic process GO:0006006 glucose metabolic process GO:0006417 regulation of translation GO:0006464 cellular protein modification process GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0007165 signal transduction GO:0007275 multicellular organism development GO:0008284 positive regulation of cell proliferation GO:0008286 insulin receptor signaling pathway GO:0008643 carbohydrate transport GO:0010748 negative regulation of plasma membrane long-chain fatty acid transport GO:0010907 positive regulation of glucose metabolic process GO:0010918 positive regulation of mitochondrial membrane potential GO:0016310 phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0030334 regulation of cell migration GO:0030335 positive regulation of cell migration GO:0031340 positive regulation of vesicle fusion GO:0032000 positive regulation of fatty acid beta-oxidation GO:0032287 peripheral nervous system myelin maintenance GO:0032869 cellular response to insulin stimulus GO:0035556 intracellular signal transduction GO:0043066 negative regulation of apoptotic process GO:0045444 fat cell differentiation GO:0045725 positive regulation of glycogen biosynthetic process GO:0046326 positive regulation of glucose import GO:0060644 mammary gland epithelial cell differentiation GO:0065002 intracellular protein transmembrane transport GO:0071156 regulation of cell cycle arrest GO:0071486 cellular response to high light intensity GO:0072659 protein localization to plasma membrane GO:0090314 positive regulation of protein targeting to membrane GO:0090630 activation of GTPase activity GO:0097473 retinal rod cell apoptotic process GO:2000147 positive regulation of cell motility GO:2001275 positive regulation of glucose import in response to insulin stimulus
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
