Details of Protein

General Information of Protein (ID: PRT01269)
Name RAC-beta serine/threonine-protein kinase (AKT2)
Synonyms   Click to Show/Hide Synonyms of This Protein
Protein kinase Akt-2; Protein kinase B beta; PKB beta; RAC-PK-beta; AKT2
Gene Name AKT2 Gene ID
208
UniProt ID
P31751
Family Transferases (EC 2)
EC Number   EC: 2.7.11.1  (Click to Show/Hide the Complete EC Tree)
Transferase
Kinase
Protein-serine/threonine kinases
EC: 2.7.11.1
  Click to Show/Hide the Molecular/Functional Data (Sequence/Structure/Function) of This Protein
Sequence
MNEVSVIKEGWLHKRGEYIKTWRPRYFLLKSDGSFIGYKERPEAPDQTLPPLNNFSVAEC
QLMKTERPRPNTFVIRCLQWTTVIERTFHVDSPDEREEWMRAIQMVANSLKQRAPGEDPM
DYKCGSPSDSSTTEEMEVAVSKARAKVTMNDFDYLKLLGKGTFGKVILVREKATGRYYAM
KILRKEVIIAKDEVAHTVTESRVLQNTRHPFLTALKYAFQTHDRLCFVMEYANGGELFFH
LSRERVFTEERARFYGAEIVSALEYLHSRDVVYRDIKLENLMLDKDGHIKITDFGLCKEG
ISDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHERLFE
LILMEEIRFPRTLSPEAKSLLAGLLKKDPKQRLGGGPSDAKEVMEHRFFLSINWQDVVQK
KLLPPFKPQVTSEVDTRYFDDEFTAQSITITPPDRYDSLGLLELDQRTHFPQFSYSASIR
E
Structure
1GZK ; 1GZN ; 1GZO ; 1MRV ; 1MRY ; 1O6K ; 1O6L ; 1P6S ; 2JDO ; 2JDR ; 2UW9 ; 2X39 ; 2XH5 ; 3D0E ; 3E87 ; 3E88 ; 3E8D
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.; 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. Phosphorylates C2CD5 on 'Ser-197' during insulin-stimulated adipocytes. AKT2 is also specifically involved in skeletal muscle differentiation, one of its substrates in this process being ANKRD2. 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'.
Regulatory Network
Full List of Metabolite(s) Regulating This Protein
      Lipids and lipid-like molecules
            5-oxo-ETE Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Metabo  Info click to show the details of this metabolite
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [1]
                      Introduced Variation 5-oxo-ETE addition (24 hours)
                      Induced Change AKT2 protein phosphorylation levels: increase
                      Summary Introduced Variation         Induced Change 
                      Disease Status Pulmonary hypertension [ICD-11: BB01]
                      Details It is reported that 5-oxo-ETE addition causes the increase of AKT2 protein phosphorylation compared with control group.
      Organic acids and derivatives
            Glutamine Click to Show/Hide the Full List of Regulating Pair(s):   1 Pair(s)
               Detailed Information Metabo  Info click to show the details of this metabolite
               Regulating Pair Experim Info click to show the details of experiment for validating this pair [2]
                      Introduced Variation Glutamine absence (16 hours)
                      Induced Change AKT2 protein abundance levels: decrease (FC = 0.73)
                      Summary Introduced Variation         Induced Change 
                      Disease Status Hepatocellular carcinoma [ICD-11: 2C12]
                      Details It is reported that glutamine absence causes the decrease of AKT2 protein abundance compared with control group.
            Leucine Click to Show/Hide the Full List of Regulating Pair(s):   2 Pair(s)
               Detailed Information Metabo  Info click to show the details of this metabolite
               Regulating Pair (1) Experim Info click to show the details of experiment for validating this pair [3]
                      Introduced Variation Leucine addition (5 hours)
                      Induced Change AKT2 protein phosphorylation levels: increase
                      Summary Introduced Variation         Induced Change 
                      Disease Status Healthy individual
                      Details It is reported that leucine addition causes the increase of AKT2 protein phosphorylation compared with control group.
               Regulating Pair (2) Experim Info click to show the details of experiment for validating this pair [4]
                      Introduced Variation Leucine decrease (24 hours)
                      Induced Change AKT2 protein phosphorylation levels: increase
                      Summary Introduced Variation         Induced Change 
                      Disease Status Hepatocellular carcinoma [ICD-11: 2C12]
                      Details It is reported that leucine decrease causes the increase of AKT2 protein phosphorylation compared with control group.
References
1 TG1019/OXE, a Galpha(i/o)-protein-coupled receptor, mediates 5-oxo-eicosatetraenoic acid-induced chemotaxis. Biochem Biophys Res Commun. 2005 Sep 9;334(4):987-95.
2 Quantitative proteomics analysis reveals glutamine deprivation activates fatty acid -oxidation pathway in HepG2 cells. Amino Acids. 2016 May;48(5):1297-307.
3 Influence of leucine on protein metabolism, phosphokinase expression, and cell proliferation in human duodenum1,3. Am J Clin Nutr. 2011 Jun;93(6):1255-62.
4 Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. Diabetes. 2011 Mar;60(3):746-56.

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