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MT000021

UniProt Annotations

Entry Information
Gene Namev-akt murine thymoma viral oncogene homolog 1
Protein EntryAKT1_HUMAN
UniProt IDP31749
SpeciesHuman
Comments
Comment typeDescription
Alternative Products Event=Alternative splicing; Named isoforms=2; Name=1; IsoId=P31749-1; Sequence=Displayed; Name=2; IsoId=P31749-2; Sequence=VSP_056180; Note=No experimental confirmation available.;
Biophysicochemical Properties Kinetic parameters: KM=52.8 uM for ATP (for purified and in vitro activated AKT1) {ECO:0000269|PubMed:16540465}; KM=0.5 uM for peptide substrate (for purified and in vitro activated AKT1) {ECO:0000269|PubMed:16540465}; KM=143.3 uM for ATP (for recombinant myristoylated AKT1 expressed and immunoprecipitated from Rat-1 cells) {ECO:0000269|PubMed:16540465}; KM=2.9 uM for peptide substrate (for recombinant myristoylated AKT1 expressed and immunoprecipitated from Rat-1 cells) {ECO:0000269|PubMed:16540465};
Catalytic Activity ATP + a protein = ADP + a phosphoprotein. {ECO:0000269|PubMed:16139227, ECO:0000269|PubMed:1718748, ECO:0000269|PubMed:1851997}.
Caution In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain. {ECO:0000305}.
Disease Breast cancer (BC) [MIM:114480]: 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. {ECO:0000269|PubMed:17611497}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease Colorectal cancer (CRC) [MIM:114500]: 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. Note=The gene represented in this entry may be involved in disease pathogenesis.
Disease Cowden syndrome 6 (CWS6) [MIM:615109]: 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. Note=The disease is caused by mutations affecting the gene represented in this entry.
Disease Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.
Disease Proteus syndrome (PROTEUSS) [MIM:176920]: 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. {ECO:0000269|PubMed:21793738}. Note=The disease is caused by mutations affecting the gene represented in this entry.
Domain Binding of the PH domain to phosphatidylinositol 3,4,5- trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3- kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction.
Domain The AGC-kinase C-terminal mediates interaction with THEM4.
Enzyme Regulation Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation. Inhibited by pyrrolopyrimidine inhibitors like aniline triazole and spiroindoline. {ECO:0000269|PubMed:18456494, ECO:0000269|PubMed:20481595, ECO:0000269|PubMed:20810279, ECO:0000269|PubMed:21392984, ECO:0000269|PubMed:9512493, ECO:0000269|PubMed:9736715}.
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.
Function 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.
Interaction Self; NbExp=2; IntAct=EBI-296087, EBI-296087; P29067:Arrb2 (xeno); NbExp=2; IntAct=EBI-296087, EBI-1636616; Q8IXJ9:ASXL1; NbExp=2; IntAct=EBI-296087, EBI-1646500; O95999:BCL10; NbExp=4; IntAct=EBI-296087, EBI-958922; Q16543:CDC37; NbExp=2; IntAct=EBI-296087, EBI-295634; Q92793:CREBBP; NbExp=3; IntAct=EBI-296087, EBI-81215; Q1W6H9:FAM110C; NbExp=2; IntAct=EBI-296087, EBI-3942563; Q9BZQ8:FAM129A; NbExp=2; IntAct=EBI-296087, EBI-6916466; P49841:GSK3B; NbExp=3; IntAct=EBI-296087, EBI-373586; P11021:HSPA5; NbExp=2; IntAct=EBI-296087, EBI-354921; Q5S007:LRRK2; NbExp=6; IntAct=EBI-296087, EBI-5323863; Q99683:MAP3K5; NbExp=2; IntAct=EBI-296087, EBI-476263; Q16539:MAPK14; NbExp=2; IntAct=EBI-296087, EBI-73946; Q00987:MDM2; NbExp=4; IntAct=EBI-296087, EBI-389668; P42345:MTOR; NbExp=2; IntAct=EBI-296087, EBI-359260; P29474:NOS3; NbExp=2; IntAct=EBI-296087, EBI-1391623; P04150:NR3C1; NbExp=5; IntAct=EBI-296087, EBI-493507; O15530:PDPK1; NbExp=3; IntAct=EBI-296087, EBI-717097; Q96S96:PEBP4; NbExp=2; IntAct=EBI-296087, EBI-8563667; P19174:PLCG1; NbExp=9; IntAct=EBI-296087, EBI-79387; O60437:PPL; NbExp=2; IntAct=EBI-296087, EBI-368321; P62136:PPP1CA; NbExp=6; IntAct=EBI-296087, EBI-357253; P67775:PPP2CA; NbExp=5; IntAct=EBI-296087, EBI-712311; P30153:PPP2R1A; NbExp=2; IntAct=EBI-296087, EBI-302388; Q05513:PRKCZ; NbExp=2; IntAct=EBI-296087, EBI-295351; P04049:RAF1; NbExp=2; IntAct=EBI-296087, EBI-365996; P23443:RPS6KB1; NbExp=2; IntAct=EBI-296087, EBI-1775921; Q15047:SETDB1; NbExp=9; IntAct=EBI-296087, EBI-79691; Q96EB6:SIRT1; NbExp=5; IntAct=EBI-296087, EBI-1802965; Q13485:SMAD4; NbExp=2; IntAct=EBI-296087, EBI-347263; Q13043:STK4; NbExp=13; IntAct=EBI-296087, EBI-367376; Q92547:TOPBP1; NbExp=2; IntAct=EBI-296087, EBI-308302; P08670:VIM; NbExp=29; IntAct=EBI-296087, EBI-353844; P03165:X (xeno); NbExp=3; IntAct=EBI-296087, EBI-7683985;
Ptm 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. {ECO:0000269|PubMed:21775285}.
Ptm 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. {ECO:0000269|PubMed:14761976, ECO:0000269|PubMed:15047712, ECO:0000269|PubMed:15718470, ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:17013611, ECO:0000269|PubMed:18456494, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20481595, ECO:0000269|PubMed:20978158, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:23799035, ECO:0000269|PubMed:8978681, ECO:0000269|PubMed:9512493, ECO:0000269|PubMed:9736715}.
Ptm Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity. Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA. 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. Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1. Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1. Ser-473 phosphorylation is enhanced by interaction with AGAP2 isoform 2 (PIKE-A). Ser-473 phosphorylation is enhanced in focal cortical dysplasias with Taylor-type balloon cells. Ser-473 phosphorylation is enhanced by signaling through activated FLT3. Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase. The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase. Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling. {ECO:0000269|PubMed:12149249, ECO:0000269|PubMed:14761976, ECO:0000269|PubMed:15047712, ECO:0000269|PubMed:15718470, ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:17013611, ECO:0000269|PubMed:18456494, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20481595, ECO:0000269|PubMed:20978158, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:23799035, ECO:0000269|PubMed:8978681, ECO:0000269|PubMed:9512493, ECO:0000269|PubMed:9736715}.
Ptm 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. {ECO:0000250, ECO:0000269|PubMed:19713527, ECO:0000269|PubMed:20059950, ECO:0000269|PubMed:21333377, ECO:0000269|PubMed:22410793}.
Similarity Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily. {ECO:0000305}.
Similarity Contains 1 AGC-kinase C-terminal domain. {ECO:0000305}.
Similarity Contains 1 PH domain. {ECO:0000255|PROSITE- ProRule:PRU00145}.
Similarity Contains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular Location Cytoplasm. Nucleus. Cell membrane. Note=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.
Subunit Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts (via the C-terminus) with CCDC88A (via its C-terminus). Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE- binding (By similarity). Interacts with AGAP2 (isoform 2/PIKE-A); the interaction occurs in the presence of guanine nucleotides. Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with CDKN1B; the interaction phosphorylates CDKN1B promoting 14-3-3 binding and cell-cycle progression. Interacts with MAP3K5 and TRAF6. Interacts with BAD, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with RAF1. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with TNK2 and CLK2. Interacts (via the C-terminus) with THEM4 (via its C-terminus). Interacts with and phosphorylated by PDPK1. {ECO:0000250, ECO:0000250|UniProtKB:P31750, ECO:0000269|PubMed:10576742, ECO:0000269|PubMed:10716693, ECO:0000269|PubMed:10926925, ECO:0000269|PubMed:10983986, ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11598301, ECO:0000269|PubMed:11839817, ECO:0000269|PubMed:12042314, ECO:0000269|PubMed:12176338, ECO:0000269|PubMed:12244301, ECO:0000269|PubMed:12964941, ECO:0000269|PubMed:14749367, ECO:0000269|PubMed:14761976, ECO:0000269|PubMed:15118108, ECO:0000269|PubMed:16139227, ECO:0000269|PubMed:16417524, ECO:0000269|PubMed:17726016, ECO:0000269|PubMed:17932490, ECO:0000269|PubMed:19592491, ECO:0000269|PubMed:19713527, ECO:0000269|PubMed:20086174, ECO:0000269|PubMed:20231902, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20682768, ECO:0000269|PubMed:21329884, ECO:0000269|PubMed:21333377, ECO:0000269|PubMed:21775285, ECO:0000269|PubMed:22629392}.
Tissue Specificity Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. {ECO:0000269|PubMed:1718748, ECO:0000269|PubMed:17932490, ECO:0000269|PubMed:20333297}.
Web Resource Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/AKT1ID355ch14q32.html";