RAC-alpha serine/threonine-protein kinase

Details

Name
RAC-alpha serine/threonine-protein kinase
Synonyms
  • 2.7.11.1
  • PKB
  • PKB alpha
  • Protein kinase B
  • Protein kinase B alpha
  • Proto-oncogene c-Akt
  • RAC
  • RAC-PK-alpha
Gene Name
AKT1
Organism
Humans
Amino acid sequence
>lcl|BSEQ0000853|RAC-alpha serine/threonine-protein kinase
MSDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQC
QLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMDF
RSGSPSDNSGAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKI
LKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLS
RERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGI
KDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFEL
ILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKK
LSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
Number of residues
480
Molecular Weight
55686.035
Theoretical pI
5.96
GO Classification
Functions
14-3-3 protein binding / ATP binding / enzyme binding / identical protein binding / kinase activity / nitric-oxide synthase regulator activity / phosphatidylinositol-3,4-bisphosphate binding / phosphatidylinositol-3,4,5-trisphosphate binding / protein kinase activity / protein serine/threonine kinase activity / protein serine/threonine/tyrosine kinase activity
Processes
activation-induced cell death of T cells / aging / apoptotic mitochondrial changes / apoptotic process / blood coagulation / cell differentiation / cell projection organization / cell proliferation / cellular protein modification process / cellular response to epidermal growth factor stimulus / cellular response to granulocyte macrophage colony-stimulating factor stimulus / cellular response to hypoxia / cellular response to insulin stimulus / cellular response to mechanical stimulus / cellular response to nerve growth factor stimulus / cellular response to organic cyclic compound / cellular response to prostaglandin E stimulus / cellular response to vascular endothelial growth factor stimulus / endocrine pancreas development / epidermal growth factor receptor signaling pathway / establishment of protein localization to mitochondrion / execution phase of apoptosis / Fc-epsilon receptor signaling pathway / fibroblast growth factor receptor signaling pathway / G-protein coupled receptor signaling pathway / gene expression / germ cell development / glucose homeostasis / glucose metabolic process / glucose transport / glycogen biosynthetic process / glycogen cell differentiation involved in embryonic placenta development / hyaluronan metabolic process / inflammatory response / innate immune response / insulin receptor signaling pathway / insulin-like growth factor receptor signaling pathway / intracellular signal transduction / intrinsic apoptotic signaling pathway / labyrinthine layer blood vessel development / lipopolysaccharide-mediated signaling pathway / maintenance of protein location in mitochondrion / mammary gland epithelial cell differentiation / maternal placenta development / membrane organization / negative regulation of apoptotic process / negative regulation of autophagy / negative regulation of cell size / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of endopeptidase activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of fatty acid beta-oxidation / negative regulation of gene expression / negative regulation of JNK cascade / negative regulation of neuron death / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / negative regulation of plasma membrane long-chain fatty acid transport / negative regulation of protein kinase activity / negative regulation of proteolysis / negative regulation of release of cytochrome c from mitochondria / neurotrophin TRK receptor signaling pathway / nitric oxide biosynthetic process / nitric oxide metabolic process / osteoblast differentiation / peptidyl-serine phosphorylation / peptidyl-threonine phosphorylation / peripheral nervous system myelin maintenance / phosphatidylinositol-mediated signaling / phosphorylation / platelet activation / positive regulation of blood vessel endothelial cell migration / positive regulation of cell growth / positive regulation of cellular protein metabolic process / positive regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle / positive regulation of endodeoxyribonuclease activity / positive regulation of endothelial cell proliferation / positive regulation of establishment of protein localization to plasma membrane / positive regulation of fat cell differentiation / positive regulation of fibroblast migration / positive regulation of glucose import / positive regulation of glucose metabolic process / positive regulation of glycogen biosynthetic process / positive regulation of lipid biosynthetic process / positive regulation of nitric oxide biosynthetic process / positive regulation of nitric-oxide synthase activity / positive regulation of peptidyl-serine phosphorylation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway / positive regulation of protein localization to nucleus / positive regulation of protein phosphorylation / positive regulation of sequence-specific DNA binding transcription factor activity / positive regulation of sodium ion transport / positive regulation of transcription from RNA polymerase II promoter / positive regulation of vasoconstriction / programmed cell death / protein autophosphorylation / protein catabolic process / protein import into nucleus, translocation / protein kinase B signaling / protein phosphorylation / protein ubiquitination / regulation of cell cycle checkpoint / regulation of cell migration / regulation of glycogen biosynthetic process / regulation of mRNA stability / regulation of myelination / regulation of neuron projection development / regulation of nitric-oxide synthase activity / regulation of translation / response to fluid shear stress / response to food / response to growth hormone / response to heat / response to insulin-like growth factor stimulus / response to oxidative stress / response to UV-A / signal transduction / small molecule metabolic process / striated muscle cell differentiation / T cell costimulation / transcription initiation from RNA polymerase II promoter / translation / vascular endothelial growth factor receptor signaling pathway
Components
cell-cell junction / ciliary basal body / cytoplasm / cytosol / microtubule cytoskeleton / mitochondrion / nucleoplasm / nucleus / plasma membrane / protein complex / spindle / vesicle
General Function
Protein serine/threonine/tyrosine kinase activity
Specific Function
AKT1 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. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53.AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Cytoplasm
Gene sequence
>lcl|BSEQ0021923|RAC-alpha serine/threonine-protein kinase (AKT1)
ATGAGCGACGTGGCTATTGTGAAGGAGGGTTGGCTGCACAAACGAGGGGAGTACATCAAG
ACCTGGCGGCCACGCTACTTCCTCCTCAAGAATGATGGCACCTTCATTGGCTACAAGGAG
CGGCCGCAGGATGTGGACCAACGTGAGGCTCCCCTCAACAACTTCTCTGTGGCGCAGTGC
CAGCTGATGAAGACGGAGCGGCCCCGGCCCAACACCTTCATCATCCGCTGCCTGCAGTGG
ACCACTGTCATCGAACGCACCTTCCATGTGGAGACTCCTGAGGAGCGGGAGGAGTGGACA
ACCGCCATCCAGACTGTGGCTGACGGCCTCAAGAAGCAGGAGGAGGAGGAGATGGACTTC
CGGTCGGGCTCACCCAGTGACAACTCAGGGGCTGAAGAGATGGAGGTGTCCCTGGCCAAG
CCCAAGCACCGCGTGACCATGAACGAGTTTGAGTACCTGAAGCTGCTGGGCAAGGGCACT
TTCGGCAAGGTGATCCTGGTGAAGGAGAAGGCCACAGGCCGCTACTACGCCATGAAGATC
CTCAAGAAGGAAGTCATCGTGGCCAAGGACGAGGTGGCCCACACACTCACCGAGAACCGC
GTCCTGCAGAACTCCAGGCACCCCTTCCTCACAGCCCTGAAGTACTCTTTCCAGACCCAC
GACCGCCTCTGCTTTGTCATGGAGTACGCCAACGGGGGCGAGCTGTTCTTCCACCTGTCC
CGGGAGCGTGTGTTCTCCGAGGACCGGGCCCGCTTCTATGGCGCTGAGATTGTGTCAGCC
CTGGACTACCTGCACTCGGAGAAGAACGTGGTGTACCGGGACCTCAAGCTGGAGAACCTC
ATGCTGGACAAGGACGGGCACATTAAGATCACAGACTTCGGGCTGTGCAAGGAGGGGATC
AAGGACGGTGCCACCATGAAGACCTTTTGCGGCACACCTGAGTACCTGGCCCCCGAGGTG
CTGGAGGACAATGACTACGGCCGTGCAGTGGACTGGTGGGGGCTGGGCGTGGTCATGTAC
GAGATGATGTGCGGTCGCCTGCCCTTCTACAACCAGGACCATGAGAAGCTTTTTGAGCTC
ATCCTCATGGAGGAGATCCGCTTCCCGCGCACGCTTGGTCCCGAGGCCAAGTCCTTGCTT
TCAGGGCTGCTCAAGAAGGACCCCAAGCAGAGGCTTGGCGGGGGCTCCGAGGACGCCAAG
GAGATCATGCAGCATCGCTTCTTTGCCGGTATCGTGTGGCAGCACGTGTACGAGAAGAAG
CTCAGCCCACCCTTCAAGCCCCAGGTCACGTCGGAGACTGACACCAGGTATTTTGATGAG
GAGTTCACGGCCCAGATGATCACCATCACACCACCTGACCAAGATGACAGCATGGAGTGT
GTGGACAGCGAGCGCAGGCCCCACTTCCCCCAGTTCTCCTACTCGGCCAGCGGCACGGCC
TGA
Chromosome Location
14
Locus
14q32.32|14q32.32
External Identifiers
ResourceLink
UniProtKB IDP31749
UniProtKB Entry NameAKT1_HUMAN
GenBank Protein ID190828
GenBank Gene IDM63167
GenAtlas IDAKT1
HGNC IDHGNC:391
General References
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Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB00171ATPinvestigational, nutraceuticalunknownDetails
DB01169Arsenic trioxideapproved, investigationalunknowninducerDetails
DB01863Inositol 1,3,4,5-TetrakisphosphateexperimentalunknownDetails
DB05971ArchexininvestigationalunknownDetails
DB06486EnzastaurininvestigationalunknownDetails
DB06641PerifosineinvestigationalunknownDetails
DB07584N-[2-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amineexperimentalunknownDetails
DB075855-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridineexperimentalunknownDetails
DB01645GenisteininvestigationalunknownDetails
DB02709ResveratrolinvestigationalunknowninhibitorDetails