RAC-alpha serine/threonine-protein kinase

RAC-alpha serine/threonine-protein kinase

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 angiogenesis11882383,15526160,15861136,21432781,21620960,31204173. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates11882383,15526160,21432781,21620960,29343641,31204173. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported11882383,15526160,21432781,21620960. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (By similarity). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (By similarity). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport11994271. AKT also regulates 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 (By similarity). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (By similarity). AKT also regulates cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase)11154276. Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis11154276. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating the mTORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB112150915,12172553. Also regulates the mTORC1 signaling pathway by catalyzing phosphorylation of CASTOR1 and DEPDC531548394,33594058. 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 (By similarity). Part of a positive feedback loop of mTORC2 signaling by mediating phosphorylation of MAPKAP1/SIN1, promoting mTORC2 activation (By similarity). 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 localization10358075. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'10358075. FOXO3 and FOXO4 are phosphorylated on equivalent sites10358075. 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)9829964. The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL19829964. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (By similarity). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth (By similarity). 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 1 (IGF1)12176338,12964941. AKT mediates the antiapoptotic effects of IGF1 (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly19934221. May be involved in the regulation of the placental development (By similarity). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO317726016. 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 translocation20086174. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation19592491. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity10576742. Phosphorylation of BAD stimulates its pro-apoptotic activity10926925. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP5323431171. Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility20471940. Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation18507042. Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization16982699. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation16139227. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation20682768. Phosphorylates PCK1 at 'Ser-90', reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor32322062. Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity32228865. Acts as a regulator of mitochondrial calcium uptake by mediating phosphorylation of MICU1 in the mitochondrial intermembrane space, impairing MICU1 maturation30504268. Acts as an inhibitor of tRNA methylation by mediating phosphorylation of the N-terminus of METTL1, thereby inhibiting METTL1 methyltransferase activity15861136. In response to LPAR1 receptor pathway activation, phosphorylates Rabin8/RAB3IP which alters its activity and phosphorylates WDR44 which induces WDR44 binding to Rab11, thereby switching Rab11 vesicular function from preciliary trafficking to endocytic recycling31204173

Quoted from UniProt’s FUNCTION annotation for P31749 (reviewed). The superscript numbers are UniProt’s own PubMed citations, kept in the sentence and in order, each linking to the paper it names.

What it acts with

STRING’s highest-confidence human functional partners. The combined score mixes several kinds of evidence, so each channel is shown separately — a partner supported by experiment is a different claim from one supported only by text mining, and for a receptor this is where its coupling appears as evidence rather than as assertion.

Where it sits in the cell

• Nucleoplasm
• Microtubules
• Principal piece
• End piece
• Primary ciliumadditional
• Basal bodyadditional
• Perinuclear thecaadditional
• Calyxadditional

Human Protein Atlas, by antibody immunofluorescence in cell lines — a different assay from the expression figures below, which are RNA.

UniProt, curated Cytoplasm · Nucleus · Cell membrane · Mitochondrion intermembrane space

Expression by cell type

Single cell type RNA, the 1 highest of those the Human Protein Atlas reports for this gene. Transcript, not protein, and a cell type rather than a tissue.

• Breast lactating cells152.8 nCPM