AKT1

The serine-threonine protein kinase encoded by the AKT1 gene is catalytically inactive in serum-starved primary and immortalized fibroblasts. AKT1 and the related AKT2 are activated by platelet-derived growth factor. The activation is rapid and specific, and it is abrogated by mutations in the pleckstrin homology domain of AKT1. It was shown that the activation occurs through phosphatidylinositol 3-kinase. In the developing nervous system AKT is a critical mediator of growth factor-induced neuronal survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase AKT1, which then phosphorylates and inactivates components of the apoptotic machinery. Mutations in this gene have been associated with the Proteus syndrome. Multiple alternatively spliced transcript variants have been found for this gene.

AKT Serine/Threonine Kinase 1

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 (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). 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 transport (PubMed:11994271). 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 (By similarity). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (By similarity). AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase) (PubMed:11154276). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis (PubMed:11154276). 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 (PubMed:12150915). 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 (PubMed:10358075). In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319' (PubMed:10358075). FOXO3 and FOXO4 are phosphorylated on equivalent sites (PubMed:10358075). 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) (PubMed: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 MCL1 (PubMed:9829964). 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 PI3P-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. 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). Signals downstream of phosphatidylinositol 3-kinase (PI3K) 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) (PubMed:12176338, PubMed:12964941). AKT mediates the antiapoptotic effects of IGF-I (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). 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 FOXO3 (PubMed:17726016). 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 (PubMed:20086174, PubMed:20231902). Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (PubMed:19592491). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity (PubMed:10576742). Phosphorylation of BAD stimulates its pro-apoptotic activity (PubMed:10926925). Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 (PubMed:23431171). Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility (PubMed:20471940). Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation (PubMed:18507042). Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization (PubMed:16982699). These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation (PubMed:16139227). Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (PubMed:20682768). 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 donor (PubMed:32322062).

Activation-induced cell death of T cells Source: MGI
Activation of protein kinase B activity Source: Reactome
Aging Source: Ensembl
Anoikis Source: ParkinsonsUK-UCL
Apoptotic mitochondrial changes Source: Ensembl
Carbohydrate transport Source: UniProtKB-KW
Cell differentiation Source: UniProtKB
Cell migration involved in sprouting angiogenesis Source: BHF-UCL
Cell population proliferation Source: UniProtKB
Cell projection organization Source: Ensembl
Cellular response to cadmium ion Source: CAFA
Cellular response to DNA damage stimulus Source: Ensembl
Cellular response to epidermal growth factor stimulus Source: Ensembl
Cellular response to granulocyte macrophage colony-stimulating factor stimulus Source: Ensembl
Cellular response to hypoxia Source: Ensembl
Cellular response to insulin stimulus Source: BHF-UCL
Cellular response to mechanical stimulus Source: Ensembl
Cellular response to nerve growth factor stimulus Source: UniProtKB
Cellular response to organic cyclic compound Source: Ensembl
Cellular response to oxidised low-density lipoprotein particle stimulus Source: BHF-UCL
Cellular response to prostaglandin E stimulus Source: Ensembl
Cellular response to reactive oxygen species Source: CAFA
Cellular response to tumor necrosis factor Source: UniProtKB
Cellular response to vascular endothelial growth factor stimulus Source: Ensembl
Cytokine-mediated signaling pathway Source: Reactome
Epidermal growth factor receptor signaling pathway Source: UniProtKB
Establishment of protein localization to mitochondrion Source: ParkinsonsUK-UCL
Excitatory postsynaptic potential Source: ParkinsonsUK-UCL
Execution phase of apoptosis Source: Ensembl
Fibroblast migration Source: BHF-UCL
Germ cell development Source: Ensembl
Glucose homeostasis Source: Ensembl
Glucose metabolic process Source: UniProtKB-KW
Glycogen biosynthetic process Source: UniProtKB-KW
Glycogen cell differentiation involved in embryonic placenta development Source: Ensembl
G protein-coupled receptor signaling pathway Source: ProtInc
Hyaluronan metabolic process Source: Ensembl
I-kappaB kinase/NF-kappaB signaling Source: CAFA
Inflammatory response Source: Ensembl
Insulin-like growth factor receptor signaling pathway Source: UniProtKB
Insulin receptor signaling pathway Source: UniProtKB
Interleukin-18-mediated signaling pathway Source: BHF-UCL
Intracellular signal transduction Source: MGI
Labyrinthine layer blood vessel development Source: Ensembl
Lipopolysaccharide-mediated signaling pathway Source: Ensembl
Maintenance of protein location in mitochondrion Source: ParkinsonsUK-UCL
Mammary gland epithelial cell differentiation Source: UniProtKB
Maternal placenta development Source: Ensembl
Negative regulation of apoptotic process Source: UniProtKB
Negative regulation of autophagy Source: BHF-UCL
Negative regulation of cell size Source: Ensembl
Negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
Negative regulation of endopeptidase activity Source: BHF-UCL
Negative regulation of extrinsic apoptotic signaling pathway in absence of ligand Source: BHF-UCL
Negative regulation of fatty acid beta-oxidation Source: BHF-UCL
Negative regulation of gene expression Source: Ensembl
Negative regulation of JNK cascade Source: Ensembl
Negative regulation of leukocyte cell-cell adhesion Source: BHF-UCL
Negative regulation of long-chain fatty acid import across plasma membrane Source: BHF-UCL
Negative regulation of lymphocyte migration Source: BHF-UCL
Negative regulation of macroautophagy Source: ParkinsonsUK-UCL
Negative regulation of neuron death Source: ParkinsonsUK-UCL
Negative regulation of Notch signaling pathway Source: Reactome
Negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway Source: BHF-UCL
Negative regulation of protein binding Source: ARUK-UCL
Negative regulation of protein kinase activity Source: BHF-UCL
Negative regulation of protein kinase activity by protein phosphorylation Source: ParkinsonsUK-UCL
Negative regulation of protein kinase B signaling Source: Reactome
Negative regulation of protein serine/threonine kinase activity Source: ARUK-UCL
Negative regulation of protein ubiquitination Source: ARUK-UCL
Negative regulation of proteolysis Source: BHF-UCL
Negative regulation of release of cytochrome c from mitochondria Source: UniProtKB
NIK/NF-kappaB signaling Source: CAFA
Nitric oxide biosynthetic process Source: ProtInc
Osteoblast differentiation Source: Ensembl
Peptidyl-serine phosphorylation Source: UniProtKB
Peptidyl-threonine phosphorylation Source: UniProtKB
Peripheral nervous system myelin maintenance Source: Ensembl
Phosphatidylinositol 3-kinase signaling Source: CAFA
Phosphorylation Source: UniProtKB
Positive regulation of apoptotic process Source: Ensembl
Positive regulation of blood vessel endothelial cell migration Source: DFLAT
Positive regulation of cell growth Source: UniProtKB
Positive regulation of cell population proliferation Source: UniProtKB
Positive regulation of cellular protein metabolic process Source: BHF-UCL
Positive regulation of cyclin-dependent protein serine/threonine kinase activity Source: BHF-UCL
Positive regulation of DNA-binding transcription factor activity Source: BHF-UCL
Positive regulation of endodeoxyribonuclease activity Source: UniProtKB
Positive regulation of endothelial cell migration Source: BHF-UCL
Positive regulation of endothelial cell proliferation Source: UniProtKB
Positive regulation of epidermal growth factor receptor signaling pathway Source: Reactome
Positive regulation of fat cell differentiation Source: BHF-UCL
Positive regulation of fibroblast migration Source: Ensembl
Positive regulation of G1/S transition of mitotic cell cycle Source: BHF-UCL
Positive regulation of gene expression Source: BHF-UCL
Positive regulation of glucose import Source: BHF-UCL
Positive regulation of glucose metabolic process Source: BHF-UCL
Positive regulation of glycogen biosynthetic process Source: BHF-UCL
Positive regulation of I-kappaB phosphorylation Source: CAFA
Positive regulation of lipid biosynthetic process Source: UniProtKB
Positive regulation of mitochondrial membrane potential Source: UniProtKB
Positive regulation of nitric oxide biosynthetic process Source: BHF-UCL
Positive regulation of nitric-oxide synthase activity Source: BHF-UCL
Positive regulation of organ growth Source: Ensembl
Positive regulation of peptidyl-serine phosphorylation Source: UniProtKB
Positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source: Ensembl
Positive regulation of protein localization to cell surface Source: Ensembl
Positive regulation of protein localization to nucleus Source: UniProtKB
Positive regulation of protein localization to plasma membrane Source: BHF-UCL
Positive regulation of protein phosphorylation Source: BHF-UCL
Positive regulation of smooth muscle cell proliferation Source: BHF-UCL
Positive regulation of sodium ion transport Source: Ensembl
Positive regulation of transcription, DNA-templated Source: CAFA
Positive regulation of transcription by RNA polymerase II Source: Ensembl
Positive regulation of vasoconstriction Source: Ensembl
Protein autophosphorylation Source: UniProtKB
Protein catabolic process Source: Ensembl
Protein import into nucleus Source: UniProtKB
Protein kinase B signaling Source: BHF-UCL
Protein phosphorylation Source: UniProtKB
Protein ubiquitination Source: Ensembl
Regulation of apoptotic process Source: UniProtKB
Regulation of cell migration Source: UniProtKB
Regulation of glycogen biosynthetic process Source: BHF-UCL
Regulation of mRNA stability Source: Reactome
Regulation of myelination Source: Ensembl
Regulation of neuron projection development Source: UniProtKB
Regulation of nitric-oxide synthase activity Source: Reactome
Regulation of signal transduction by p53 class mediator Source: Reactome
Regulation of translation Source: UniProtKB-KW
Regulation of type B pancreatic cell development Source: Reactome
Response to fluid shear stress Source: BHF-UCL
Response to food Source: Ensembl
Response to growth hormone Source: AgBase
Response to heat Source: ProtInc
Response to insulin-like growth factor stimulus Source: AgBase
Response to oxidative stress Source: ParkinsonsUK-UCL
Response to UV-A Source: BHF-UCL
Signal transduction Source: UniProtKB
Sphingosine-1-phosphate receptor signaling pathway Source: BHF-UCL
Spinal cord development Source: Ensembl
Striated muscle cell differentiation Source: Ensembl
T cell costimulation Source: Reactome
Tetrahydrobiopterin metabolic process Source: Reactome
TOR signaling Source: ParkinsonsUK-UCL
Translation Source: Ensembl

Nucleus; Cytoplasm; Cell membrane. Nucleus after activation by integrin-linked protein kinase 1 (ILK1). Nuclear translocation is enhanced by interaction with TCL1A. Phosphorylation on Tyr-176 by TNK2 results in its localization to the cell membrane where it is targeted for further phosphorylations on Thr-308 and Ser-473 leading to its activation and the activated form translocates to the nucleus. Colocalizes with WDFY2 in intracellular vesicles (PubMed:16792529).

Breast cancer (BC): A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case.
Colorectal cancer (CRC): A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.
Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.
Proteus syndrome (PROTEUSS): A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes.
Cowden syndrome 6 (CWS6): A form of Cowden syndrome, a hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid.

O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1. O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site.
Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity (PubMed:12149249, PubMed:14761976, PubMed:15047712, PubMed:16266983, PubMed:17013611, PubMed:20978158, PubMed:9736715, PubMed:23799035, PubMed:8978681, PubMed:28147277). Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA (PubMed:20333297). This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation (PubMed:9512493). Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1 (PubMed:21464307, PubMed:8978681). Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1 (PubMed:15718470, PubMed:18456494, PubMed:20481595, PubMed:8978681). Ser-473 phosphorylation is enhanced by interaction with AGAP2 isoform 2 (PIKE-A) (PubMed:14761976). Ser-473 phosphorylation is enhanced in focal cortical dysplasias with Taylor-type balloon cells (PubMed:17013611). Ser-473 phosphorylation is enhanced by signaling through activated FLT3 (By similarity). Ser-473 is dephosphorylated by PHLPP (PubMed:28147277). Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase (PubMed:21329884). The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase (PubMed:21329884). Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (PubMed:9512493).
Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome (By similarity). Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation. When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. Also ubiquitinated by TRIM13 leading to its proteasomal degradation. Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation.
Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition.
Cleavage by caspase-3/CASP3 (By similarity). Cleaved at the caspase-3 consensus site Asp-462 during apoptosis, resulting in down-regulation of the AKT signaling pathway and decreased cell survival (PubMed:23152800).