Names & Taxonomy

Uniprot ID:
P31751
Entry Name:
AKT2_HUMAN
Status:
reviewed
Protein Names:
RAC-beta serine/threonine-protein kinase (EC 2.7.11.1) (Protein kinase Akt-2) (Protein kinase B beta) (PKB beta) (RAC-PK-beta)
Gene Names:
AKT2
Gene Names Primary:
AKT2
Organism:
Homo sapiens (Human)

Structure

Length:
481
Sequence:
MNEVSVIKEGWLHKRGEYIKTWRPRYFLLKSDGSFIGYKERPEAPDQTLPPLNNFSVAECQLMKTERPRPNTFVIRCLQWTTVIERTFHVDSPDEREEWMRAIQMVANSLKQRAPGEDPMDYKCGSPSDSSTTEEMEVAVSKARAKVTMNDFDYLKLLGKGTFGKVILVREKATGRYYAMKILRKEVIIAKDEVAHTVTESRVLQNTRHPFLTALKYAFQTHDRLCFVMEYANGGELFFHLSRERVFTEERARFYGAEIVSALEYLHSRDVVYRDIKLENLMLDKDGHIKITDFGLCKEGISDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHERLFELILMEEIRFPRTLSPEAKSLLAGLLKKDPKQRLGGGPSDAKEVMEHRFFLSINWQDVVQKKLLPPFKPQVTSEVDTRYFDDEFTAQSITITPPDRYDSLGLLELDQRTHFPQFSYSASIRE
Proteomes:
UP000005640

Subcellular location

Subcellular Location:
Cytoplasm. Nucleus. Cell membrane; Peripheral membrane protein. Early endosome

Function

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'.
Catalytic Activity:
ATP + a protein = ADP + a phosphoprotein.
Kinetics:
BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=358.4 uM for ATP (for purified and in vitro activated AKT2)
Enzyme Regulation:
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.
Active Site:
ACT_SITE 275 275 Proton acceptor.
Gene Ontology Go:
cell cortex
cytosol
early endosome
insulin-responsive compartment
nucleoplasm
nucleus
plasma membrane
ruffle membrane
ATP binding
protein serine/threonine kinase activity
activation of GTPase activity
carbohydrate transport
cellular protein modification process
cellular response to insulin stimulus
cellular response to organic cyclic compound
fat cell differentiation
glucose metabolic process
glycogen biosynthetic process
insulin receptor signaling pathway
intracellular protein transmembrane transport
intracellular signal transduction
mammary gland epithelial cell differentiation
membrane organization
negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
negative regulation of plasma membrane long-chain fatty acid transport
negative regulation of RNA splicing
peptidyl-serine phosphorylation
peripheral nervous system myelin maintenance
positive regulation of cell migration
positive regulation of cell motility
positive regulation of fatty acid beta-oxidation
positive regulation of glucose import
positive regulation of glucose import in response to insulin stimulus
positive regulation of glucose metabolic process
positive regulation of glycogen biosynthetic process
positive regulation of nitric oxide biosynthetic process
positive regulation of peptidyl-serine phosphorylation
positive regulation of positive chemotaxis
positive regulation of protein phosphorylation
positive regulation of protein targeting to membrane
positive regulation of signal transduction
positive regulation of transcription from RNA polymerase II promoter
positive regulation of vesicle fusion
protein kinase B signaling
protein localization to plasma membrane
regulation of cell cycle arrest
regulation of cell migration
regulation of translation
response to muscle activity
response to nutrient levels
response to osmotic stress
signal transduction
Gene Ontology Biological Process:
activation of GTPase activity
carbohydrate transport
cellular protein modification process
cellular response to insulin stimulus
cellular response to organic cyclic compound
fat cell differentiation
glucose metabolic process
glycogen biosynthetic process
insulin receptor signaling pathway
intracellular protein transmembrane transport
intracellular signal transduction
mammary gland epithelial cell differentiation
membrane organization
negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
negative regulation of plasma membrane long-chain fatty acid transport
negative regulation of RNA splicing
peptidyl-serine phosphorylation
peripheral nervous system myelin maintenance
positive regulation of cell migration
positive regulation of cell motility
positive regulation of fatty acid beta-oxidation
positive regulation of glucose import
positive regulation of glucose import in response to insulin stimulus
positive regulation of glucose metabolic process
positive regulation of glycogen biosynthetic process
positive regulation of nitric oxide biosynthetic process
positive regulation of peptidyl-serine phosphorylation
positive regulation of positive chemotaxis
positive regulation of protein phosphorylation
positive regulation of protein targeting to membrane
positive regulation of signal transduction
positive regulation of transcription from RNA polymerase II promoter
positive regulation of vesicle fusion
protein kinase B signaling
protein localization to plasma membrane
regulation of cell cycle arrest
regulation of cell migration
regulation of translation
response to muscle activity
response to nutrient levels
response to osmotic stress
signal transduction
Gene Ontology Molecular Function:
ATP binding
protein serine/threonine kinase activity
Gene Ontology Cellular Component:
cell cortex
cytosol
early endosome
insulin-responsive compartment
nucleoplasm
nucleus
plasma membrane
ruffle membrane
Keywords:
3D-structure
ATP-binding
Acetylation
Alternative splicing
Apoptosis
Carbohydrate metabolism
Cell membrane
Complete proteome
Cytoplasm
Developmental protein
Diabetes mellitus
Disease mutation
Disulfide bond
Endosome
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
Interacts With:
P49841; P08238; P08670

Publication

PubMed ID:
1801921 1409633 14702039 15057824 15489334 9512493 10983986 15890450 16792529 16540465 17565718 18669648 20059950 19139280 19690332 19713527 20167810 21269460 21620960 21432781 21737686 22223895 24275569 12086620 12434148 12517337 14755158 17275837 18800763 19179070 15166380 17344846 19164855 21979934