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Protein

RAC-alpha serine/threonine-protein kinase

Gene

AKT1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 PI3P-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 (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). 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.

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.Curated

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.3 Publications

Activity regulationi

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.6 Publications

Kineticsi

  1. KM=52.8 µM for ATP (for purified and in vitro activated AKT1)1 Publication
  2. KM=0.5 µM for peptide substrate (for purified and in vitro activated AKT1)1 Publication
  3. KM=143.3 µM for ATP (for recombinant myristoylated AKT1 expressed and immunoprecipitated from Rat-1 cells)1 Publication
  4. KM=2.9 µM for peptide substrate (for recombinant myristoylated AKT1 expressed and immunoprecipitated from Rat-1 cells)1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei53Inositol-(1,3,4,5)-tetrakisphosphate1
    Binding sitei86Inositol-(1,3,4,5)-tetrakisphosphate1
    Binding sitei161Inhibitor; via amide nitrogen1
    Binding sitei179ATPPROSITE-ProRule annotation1
    Binding sitei230Inhibitor; via amide nitrogen1
    Binding sitei234Inhibitor1
    Active sitei274Proton acceptorPROSITE-ProRule annotation1
    Binding sitei292Inhibitor1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi156 – 164ATPPROSITE-ProRule annotation9

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionDevelopmental protein, Kinase, Serine/threonine-protein kinase, Transferase
    Biological processApoptosis, Carbohydrate metabolism, Glucose metabolism, Glycogen biosynthesis, Glycogen metabolism, Neurogenesis, Sugar transport, Translation regulation, Transport
    LigandATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.11.1 2681
    ReactomeiR-HSA-111447 Activation of BAD and translocation to mitochondria
    R-HSA-1257604 PIP3 activates AKT signaling
    R-HSA-1358803 Downregulation of ERBB2:ERBB3 signaling
    R-HSA-1445148 Translocation of SLC2A4 (GLUT4) to the plasma membrane
    R-HSA-1474151 Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
    R-HSA-165159 mTOR signalling
    R-HSA-198323 AKT phosphorylates targets in the cytosol
    R-HSA-198693 AKT phosphorylates targets in the nucleus
    R-HSA-199418 Negative regulation of the PI3K/AKT network
    R-HSA-203615 eNOS activation
    R-HSA-211163 AKT-mediated inactivation of FOXO1A
    R-HSA-354192 Integrin alphaIIb beta3 signaling
    R-HSA-3769402 Deactivation of the beta-catenin transactivating complex
    R-HSA-389357 CD28 dependent PI3K/Akt signaling
    R-HSA-389513 CTLA4 inhibitory signaling
    R-HSA-392451 G beta:gamma signalling through PI3Kgamma
    R-HSA-450385 Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA
    R-HSA-450604 KSRP (KHSRP) binds and destabilizes mRNA
    R-HSA-5218920 VEGFR2 mediated vascular permeability
    R-HSA-5628897 TP53 Regulates Metabolic Genes
    R-HSA-5674400 Constitutive Signaling by AKT1 E17K in Cancer
    R-HSA-6785807 Interleukin-4 and Interleukin-13 signaling
    R-HSA-6804757 Regulation of TP53 Degradation
    R-HSA-6804758 Regulation of TP53 Activity through Acetylation
    R-HSA-6804759 Regulation of TP53 Activity through Association with Co-factors
    R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
    R-HSA-69202 Cyclin E associated events during G1/S transition
    R-HSA-69656 Cyclin A:Cdk2-associated events at S phase entry
    R-HSA-8849469 PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1
    R-HSA-8876198 RAB GEFs exchange GTP for GDP on RABs
    R-HSA-8941332 RUNX2 regulates genes involved in cell migration
    R-HSA-8948751 Regulation of PTEN stability and activity
    R-HSA-9604323 Negative regulation of NOTCH4 signaling
    SABIO-RKiP31749
    SignaLinkiP31749
    SIGNORiP31749

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    RAC-alpha serine/threonine-protein kinase (EC:2.7.11.1)
    Alternative name(s):
    Protein kinase B
    Short name:
    PKB
    Protein kinase B alpha
    Short name:
    PKB alpha
    Proto-oncogene c-Akt
    RAC-PK-alpha
    Gene namesi
    Name:AKT1
    Synonyms:PKB, RAC
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 14

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000142208.15
    HGNCiHGNC:391 AKT1
    MIMi164730 gene
    neXtProtiNX_P31749

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Membrane, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Breast cancer (BC)1 Publication
    Disease susceptibility is associated with variations affecting the gene represented in this entry.
    Disease descriptionA 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.
    See also OMIM:114480
    Colorectal cancer (CRC)
    The gene represented in this entry may be involved in disease pathogenesis.
    Disease descriptionA 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.
    See also OMIM:114500
    Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.
    Proteus syndrome (PROTEUSS)2 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA 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.
    See also OMIM:176920
    Cowden syndrome 6 (CWS6)1 Publication
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA 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.
    See also OMIM:615109
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_06979125R → C in CWS6. 1 PublicationCorresponds to variant dbSNP:rs397514644EnsemblClinVar.1
    Natural variantiVAR_069792435T → P in CWS6. 1 PublicationCorresponds to variant dbSNP:rs397514645EnsemblClinVar.1

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi8K → R: Substantial reduction of ubiquitination, phosphorylation at T-308 and S-473, AKT activation as well as IGF1-induced membrane recruitment. Decrease in ubiquitination and phosphorylation at T-308 as well as impaired association with the membrane; when associated with K-17. 1 Publication1
    Mutagenesisi14K → A: Impairs interaction with PtdIns(3,4,5)P3 and PtdIns(3,4)P2. 3 Publications1
    Mutagenesisi14K → Q: Substantial reduction of phosphorylation at T-308 and S-473, loss of AKT activation, and loss of binding to PIP3 as well as IGF1-induced membrane recruitment. 3 Publications1
    Mutagenesisi14K → R: Substantial reduction of ubiquitination, phosphorylation at T-308 and S-473, AKT activation, loss of binding to PIP3 as well as IGF1-induced membrane recruitment. 3 Publications1
    Mutagenesisi17E → K: No effect on membrane localization. Loss of membrane localization; when associated with Q-20. 1 Publication1
    Mutagenesisi20K → Q: Substantial reduction of phosphorylation at T-308 and S-473, reduced AKT activation, and reduced binding to PIP3 as well as IGF1-induced membrane recruitment. Loss of membrane localization; when associated with K-17. 1 Publication1
    Mutagenesisi20K → R: Slight increase of phosphorylation at T-308 and S-473. 1 Publication1
    Mutagenesisi25R → A or C: Impairs interaction with PtdIns(3,4,5)P3 and PtdIns(3,4)P2. 1 Publication1
    Mutagenesisi86R → A: Impairs interaction with PtdIns(3,4,5)P3 and PtdIns(3,4)P2. 1 Publication1
    Mutagenesisi176Y → F: Significant loss of interaction with TNK2. Loss of membrane localization. Significant reduction in phosphorylation on Ser-473. 1 Publication1
    Mutagenesisi305T → A: Reduces O-GlcNAc levels; Reduces O-GlcNAc levels even more; when associated with A-312. 1 Publication1
    Mutagenesisi305T → Y: Abolishes phosphorylation at Thr-308. 1 Publication1
    Mutagenesisi308T → D: 5-fold activation and 18-fold activation; when associated with D-473. 2 Publications1
    Mutagenesisi312T → A: Reduces O-GlcNAc levels; Reduces O-GlcNAc levels even more; when associated with A-305. 1 Publication1
    Mutagenesisi312T → Y: Abolishes phosphorylation at Thr-308. 1 Publication1
    Mutagenesisi473S → D: 7-fold activation and 25-fold activation; when associated with D-308. 2 Publications1
    Mutagenesisi474Y → F: 55% inhibition of activation. 1 Publication1

    Keywords - Diseasei

    Disease mutation, Proto-oncogene

    Organism-specific databases

    DisGeNETi207
    GeneReviewsiAKT1
    MalaCardsiAKT1
    MIMi114480 phenotype
    114500 phenotype
    176920 phenotype
    615109 phenotype
    OpenTargetsiENSG00000142208
    Orphaneti201 Cowden syndrome
    744 Proteus syndrome
    PharmGKBiPA24684

    Chemistry databases

    ChEMBLiCHEMBL4282
    DrugBankiDB00171 Adenosine triphosphate
    DB01169 Arsenic trioxide
    GuidetoPHARMACOLOGYi1479

    Polymorphism and mutation databases

    BioMutaiAKT1
    DMDMi60391226

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000856051 – 480RAC-alpha serine/threonine-protein kinaseAdd BLAST480

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei14N6-acetyllysine1 Publication1
    Modified residuei20N6-acetyllysine1 Publication1
    Disulfide bondi60 ↔ 771 Publication
    Modified residuei124PhosphoserineCombined sources1
    Modified residuei126Phosphoserine; alternateCombined sources1
    Glycosylationi126O-linked (GlcNAc) serine; alternate1 Publication1
    Modified residuei129Phosphoserine; alternateCombined sources1
    Glycosylationi129O-linked (GlcNAc) serine; alternate1 Publication1
    Modified residuei176Phosphotyrosine; by TNK21 Publication1
    Cross-linki284Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
    Disulfide bondi296 ↔ 310By similarity
    Glycosylationi305O-linked (GlcNAc) threonine1 Publication1
    Modified residuei308Phosphothreonine; by IKKE, PDPK1 and TBK17 Publications1
    Glycosylationi312O-linked (GlcNAc) threonine1 Publication1
    Modified residuei448PhosphothreonineCombined sources1
    Modified residuei450PhosphothreonineCombined sources1
    Modified residuei473Phosphoserine; by IKKE, MTOR and TBK1; alternate11 Publications1
    Glycosylationi473O-linked (GlcNAc) serine; alternateBy similarity1
    Modified residuei474Phosphotyrosine1 Publication1

    Post-translational modificationi

    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.14 Publications
    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.15 Publications
    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.By similarity4 Publications
    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.1 Publication

    Keywords - PTMi

    Acetylation, Disulfide bond, Glycoprotein, Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    EPDiP31749
    MaxQBiP31749
    PaxDbiP31749
    PeptideAtlasiP31749
    PRIDEiP31749
    ProteomicsDBi54800

    PTM databases

    iPTMnetiP31749
    PhosphoSitePlusiP31749

    Miscellaneous databases

    PMAP-CutDBiP31749

    Expressioni

    Tissue specificityi

    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.3 Publications

    Gene expression databases

    BgeeiENSG00000142208 Expressed in 215 organ(s), highest expression level in left adrenal gland
    CleanExiHS_AKT1
    ExpressionAtlasiP31749 baseline and differential
    GenevisibleiP31749 HS

    Organism-specific databases

    HPAiCAB003765
    HPA002891

    Interactioni

    Subunit structurei

    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. Interacts with PA2G4 (By similarity). Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation (PubMed:24784001). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529). Forms a complex with WDFY2 and FOXO1 (By similarity). Interacts with FAM168A (PubMed:23251525). Interacts with SYAP1 (via phosphorylated form and BSD domain); this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1 (PubMed:23300339). Interacts with PKHM3 (By similarity).By similarity33 Publications

    Binary interactionsi

    GO - Molecular functioni

    Protein-protein interaction databases

    BioGridi106710, 320 interactors
    CORUMiP31749
    DIPiDIP-24269N
    ELMiP31749
    IntActiP31749, 163 interactors
    MINTiP31749
    STRINGi9606.ENSP00000270202

    Chemistry databases

    BindingDBiP31749

    Structurei

    Secondary structure

    1480
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliP31749
    SMRiP31749
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP31749

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini5 – 108PHPROSITE-ProRule annotationAdd BLAST104
    Domaini150 – 408Protein kinasePROSITE-ProRule annotationAdd BLAST259
    Domaini409 – 480AGC-kinase C-terminalAdd BLAST72

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni14 – 19Inositol-(1,3,4,5)-tetrakisphosphate binding6
    Regioni23 – 25Inositol-(1,3,4,5)-tetrakisphosphate binding3
    Regioni228 – 230Inhibitor binding3

    Domaini

    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.
    The AGC-kinase C-terminal mediates interaction with THEM4.

    Sequence similaritiesi

    Phylogenomic databases

    eggNOGiKOG0598 Eukaryota
    ENOG410XNPH LUCA
    GeneTreeiENSGT00930000150811
    HOGENOMiHOG000233033
    HOVERGENiHBG108317
    InParanoidiP31749
    KOiK04456
    OMAiQDDSMES
    OrthoDBiEOG091G06FF
    PhylomeDBiP31749
    TreeFamiTF102004

    Family and domain databases

    CDDicd01241 PH_PKB, 1 hit
    cd05594 STKc_PKB_alpha, 1 hit
    Gene3Di2.30.29.30, 1 hit
    InterProiView protein in InterPro
    IPR000961 AGC-kinase_C
    IPR034676 Akt1
    IPR011009 Kinase-like_dom_sf
    IPR011993 PH-like_dom_sf
    IPR001849 PH_domain
    IPR039026 PH_PKB
    IPR017892 Pkinase_C
    IPR000719 Prot_kinase_dom
    IPR017441 Protein_kinase_ATP_BS
    IPR039027 RAC_alpha/beta
    IPR008271 Ser/Thr_kinase_AS
    PANTHERiPTHR24356:SF176 PTHR24356:SF176, 1 hit
    PfamiView protein in Pfam
    PF00169 PH, 1 hit
    PF00069 Pkinase, 1 hit
    PF00433 Pkinase_C, 1 hit
    SMARTiView protein in SMART
    SM00233 PH, 1 hit
    SM00133 S_TK_X, 1 hit
    SM00220 S_TKc, 1 hit
    SUPFAMiSSF56112 SSF56112, 1 hit
    PROSITEiView protein in PROSITE
    PS51285 AGC_KINASE_CTER, 1 hit
    PS50003 PH_DOMAIN, 1 hit
    PS00107 PROTEIN_KINASE_ATP, 1 hit
    PS50011 PROTEIN_KINASE_DOM, 1 hit
    PS00108 PROTEIN_KINASE_ST, 1 hit

    Sequences (2+)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

    This entry has 2 described isoforms and 4 potential isoforms that are computationally mapped.Show allAlign All

    Isoform 1 (identifier: P31749-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide
            10         20         30         40         50
    MSDVAIVKEG WLHKRGEYIK TWRPRYFLLK NDGTFIGYKE RPQDVDQREA
    60 70 80 90 100
    PLNNFSVAQC QLMKTERPRP NTFIIRCLQW TTVIERTFHV ETPEEREEWT
    110 120 130 140 150
    TAIQTVADGL KKQEEEEMDF RSGSPSDNSG AEEMEVSLAK PKHRVTMNEF
    160 170 180 190 200
    EYLKLLGKGT FGKVILVKEK ATGRYYAMKI LKKEVIVAKD EVAHTLTENR
    210 220 230 240 250
    VLQNSRHPFL TALKYSFQTH DRLCFVMEYA NGGELFFHLS RERVFSEDRA
    260 270 280 290 300
    RFYGAEIVSA LDYLHSEKNV VYRDLKLENL MLDKDGHIKI TDFGLCKEGI
    310 320 330 340 350
    KDGATMKTFC GTPEYLAPEV LEDNDYGRAV DWWGLGVVMY EMMCGRLPFY
    360 370 380 390 400
    NQDHEKLFEL ILMEEIRFPR TLGPEAKSLL SGLLKKDPKQ RLGGGSEDAK
    410 420 430 440 450
    EIMQHRFFAG IVWQHVYEKK LSPPFKPQVT SETDTRYFDE EFTAQMITIT
    460 470 480
    PPDQDDSMEC VDSERRPHFP QFSYSASGTA
    Length:480
    Mass (Da):55,686
    Last modified:February 1, 2005 - v2
    Checksum:i6EAFF4F8AD436714
    GO
    Isoform 2 (identifier: P31749-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-62: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:418
    Mass (Da):48,347
    Checksum:i671C0EB4BDF8F45F
    GO

    Computationally mapped potential isoform sequencesi

    There are 4 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    G3V3X1G3V3X1_HUMAN
    RAC-alpha serine/threonine-protein ...
    AKT1
    170Annotation score:
    A0A087WY56A0A087WY56_HUMAN
    RAC-alpha serine/threonine-protein ...
    AKT1
    146Annotation score:
    G3V2I6G3V2I6_HUMAN
    RAC-alpha serine/threonine-protein ...
    AKT1
    184Annotation score:
    G3V4I6G3V4I6_HUMAN
    RAC-alpha serine/threonine-protein ...
    AKT1
    91Annotation score:

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti173 – 174GR → A in CAA43372 (PubMed:1718748).Curated2
    Sequence conflicti202L → Q in CAA43372 (PubMed:1718748).Curated1
    Sequence conflicti212A → R in CAA43372 (PubMed:1718748).Curated1
    Sequence conflicti246S → A in CAA43372 (PubMed:1718748).Curated1
    Sequence conflicti409A → T in CAA43372 (PubMed:1718748).Curated1
    Sequence conflicti476A → P in CAA43372 (PubMed:1718748).Curated1
    Sequence conflicti478G → A in CAA43372 (PubMed:1718748).Curated1
    Sequence conflicti478G → S in AAA36539 (PubMed:1851997).Curated1
    Sequence conflicti478G → S in AAL55732 (PubMed:11508278).Curated1
    Sequence conflicti478G → S in BAG36922 (PubMed:14702039).Curated1
    Sequence conflicti478G → S in BAG70056 (PubMed:19054851).Curated1
    Sequence conflicti478G → S in BAG70181 (PubMed:19054851).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_05542217E → K in PROTEUSS and breast cancer; also detected in colorectal and ovarian cancer; somatic mutation; results in increased phosphorylation at T-308 and higher basal ubiquitination; the mutant protein is more efficiently recruited to the plasma membrane; alters phosphatidylinositiol phosphates lipid specificity of the AKT1 PH domain. 4 PublicationsCorresponds to variant dbSNP:rs121434592EnsemblClinVar.1
    Natural variantiVAR_06979125R → C in CWS6. 1 PublicationCorresponds to variant dbSNP:rs397514644EnsemblClinVar.1
    Natural variantiVAR_051617167V → A. Corresponds to variant dbSNP:rs11555433Ensembl.1
    Natural variantiVAR_069792435T → P in CWS6. 1 PublicationCorresponds to variant dbSNP:rs397514645EnsemblClinVar.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0561801 – 62Missing in isoform 2. 1 PublicationAdd BLAST62

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    M63167 mRNA Translation: AAA36539.1
    AF283830
    , AF283819, AF283820, AF283821, AF283822, AF283823, AF283824, AF283825, AF283826, AF283827, AF283828, AF283829 Genomic DNA Translation: AAL55732.1
    AK299310 mRNA Translation: BAH12997.1
    AK314256 mRNA Translation: BAG36922.1
    AB451242 mRNA Translation: BAG70056.1
    AB451367 mRNA Translation: BAG70181.1
    AL583722 Genomic DNA No translation available.
    AL590327 Genomic DNA No translation available.
    BC000479 mRNA Translation: AAH00479.1
    BC084538 mRNA Translation: AAH84538.1
    X61037 mRNA Translation: CAA43372.1
    CCDSiCCDS9994.1 [P31749-1]
    PIRiA39360
    RefSeqiNP_001014431.1, NM_001014431.1 [P31749-1]
    NP_001014432.1, NM_001014432.1 [P31749-1]
    NP_005154.2, NM_005163.2 [P31749-1]
    XP_005267458.1, XM_005267401.1
    UniGeneiHs.525622

    Genome annotation databases

    EnsembliENST00000349310; ENSP00000270202; ENSG00000142208 [P31749-1]
    ENST00000402615; ENSP00000385326; ENSG00000142208 [P31749-1]
    ENST00000407796; ENSP00000384293; ENSG00000142208 [P31749-1]
    ENST00000554581; ENSP00000451828; ENSG00000142208 [P31749-1]
    ENST00000554848; ENSP00000451166; ENSG00000142208 [P31749-1]
    ENST00000555528; ENSP00000450688; ENSG00000142208 [P31749-1]
    GeneIDi207
    KEGGihsa:207
    UCSCiuc001ypk.4 human [P31749-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Cross-referencesi

    Web resourcesi

    Atlas of Genetics and Cytogenetics in Oncology and Haematology

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    M63167 mRNA Translation: AAA36539.1
    AF283830
    , AF283819, AF283820, AF283821, AF283822, AF283823, AF283824, AF283825, AF283826, AF283827, AF283828, AF283829 Genomic DNA Translation: AAL55732.1
    AK299310 mRNA Translation: BAH12997.1
    AK314256 mRNA Translation: BAG36922.1
    AB451242 mRNA Translation: BAG70056.1
    AB451367 mRNA Translation: BAG70181.1
    AL583722 Genomic DNA No translation available.
    AL590327 Genomic DNA No translation available.
    BC000479 mRNA Translation: AAH00479.1
    BC084538 mRNA Translation: AAH84538.1
    X61037 mRNA Translation: CAA43372.1
    CCDSiCCDS9994.1 [P31749-1]
    PIRiA39360
    RefSeqiNP_001014431.1, NM_001014431.1 [P31749-1]
    NP_001014432.1, NM_001014432.1 [P31749-1]
    NP_005154.2, NM_005163.2 [P31749-1]
    XP_005267458.1, XM_005267401.1
    UniGeneiHs.525622

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1H10X-ray1.40A1-123[»]
    1UNPX-ray1.65A1-121[»]
    1UNQX-ray0.98A1-123[»]
    1UNRX-ray1.25A1-123[»]
    2UVMX-ray1.94A1-123[»]
    2UZRX-ray1.94A1-123[»]
    2UZSX-ray2.46A1-123[»]
    3CQUX-ray2.20A144-480[»]
    3CQWX-ray2.00A144-480[»]
    3MV5X-ray2.47A144-480[»]
    3MVHX-ray2.01A144-480[»]
    3O96X-ray2.70A2-443[»]
    3OCBX-ray2.70A/B144-480[»]
    3OW4X-ray2.60A/B144-480[»]
    3QKKX-ray2.30A144-480[»]
    3QKLX-ray1.90A144-480[»]
    3QKMX-ray2.20A144-480[»]
    4EJNX-ray2.19A2-446[»]
    4EKKX-ray2.80A/B144-480[»]
    4EKLX-ray2.00A144-480[»]
    4GV1X-ray1.49A144-480[»]
    5KCVX-ray2.70A2-446[»]
    6BUUX-ray2.40A/B144-480[»]
    6C0IX-ray2.40A/B144-480[»]
    6CCYX-ray2.18A144-466[»]
    ProteinModelPortaliP31749
    SMRiP31749
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi106710, 320 interactors
    CORUMiP31749
    DIPiDIP-24269N
    ELMiP31749
    IntActiP31749, 163 interactors
    MINTiP31749
    STRINGi9606.ENSP00000270202

    Chemistry databases

    BindingDBiP31749
    ChEMBLiCHEMBL4282
    DrugBankiDB00171 Adenosine triphosphate
    DB01169 Arsenic trioxide
    GuidetoPHARMACOLOGYi1479

    PTM databases

    iPTMnetiP31749
    PhosphoSitePlusiP31749

    Polymorphism and mutation databases

    BioMutaiAKT1
    DMDMi60391226

    Proteomic databases

    EPDiP31749
    MaxQBiP31749
    PaxDbiP31749
    PeptideAtlasiP31749
    PRIDEiP31749
    ProteomicsDBi54800

    Protocols and materials databases

    DNASUi207
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000349310; ENSP00000270202; ENSG00000142208 [P31749-1]
    ENST00000402615; ENSP00000385326; ENSG00000142208 [P31749-1]
    ENST00000407796; ENSP00000384293; ENSG00000142208 [P31749-1]
    ENST00000554581; ENSP00000451828; ENSG00000142208 [P31749-1]
    ENST00000554848; ENSP00000451166; ENSG00000142208 [P31749-1]
    ENST00000555528; ENSP00000450688; ENSG00000142208 [P31749-1]
    GeneIDi207
    KEGGihsa:207
    UCSCiuc001ypk.4 human [P31749-1]

    Organism-specific databases

    CTDi207
    DisGeNETi207
    EuPathDBiHostDB:ENSG00000142208.15
    GeneCardsiAKT1
    GeneReviewsiAKT1
    HGNCiHGNC:391 AKT1
    HPAiCAB003765
    HPA002891
    MalaCardsiAKT1
    MIMi114480 phenotype
    114500 phenotype
    164730 gene
    176920 phenotype
    615109 phenotype
    neXtProtiNX_P31749
    OpenTargetsiENSG00000142208
    Orphaneti201 Cowden syndrome
    744 Proteus syndrome
    PharmGKBiPA24684
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG0598 Eukaryota
    ENOG410XNPH LUCA
    GeneTreeiENSGT00930000150811
    HOGENOMiHOG000233033
    HOVERGENiHBG108317
    InParanoidiP31749
    KOiK04456
    OMAiQDDSMES
    OrthoDBiEOG091G06FF
    PhylomeDBiP31749
    TreeFamiTF102004

    Enzyme and pathway databases

    BRENDAi2.7.11.1 2681
    ReactomeiR-HSA-111447 Activation of BAD and translocation to mitochondria
    R-HSA-1257604 PIP3 activates AKT signaling
    R-HSA-1358803 Downregulation of ERBB2:ERBB3 signaling
    R-HSA-1445148 Translocation of SLC2A4 (GLUT4) to the plasma membrane
    R-HSA-1474151 Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
    R-HSA-165159 mTOR signalling
    R-HSA-198323 AKT phosphorylates targets in the cytosol
    R-HSA-198693 AKT phosphorylates targets in the nucleus
    R-HSA-199418 Negative regulation of the PI3K/AKT network
    R-HSA-203615 eNOS activation
    R-HSA-211163 AKT-mediated inactivation of FOXO1A
    R-HSA-354192 Integrin alphaIIb beta3 signaling
    R-HSA-3769402 Deactivation of the beta-catenin transactivating complex
    R-HSA-389357 CD28 dependent PI3K/Akt signaling
    R-HSA-389513 CTLA4 inhibitory signaling
    R-HSA-392451 G beta:gamma signalling through PI3Kgamma
    R-HSA-450385 Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA
    R-HSA-450604 KSRP (KHSRP) binds and destabilizes mRNA
    R-HSA-5218920 VEGFR2 mediated vascular permeability
    R-HSA-5628897 TP53 Regulates Metabolic Genes
    R-HSA-5674400 Constitutive Signaling by AKT1 E17K in Cancer
    R-HSA-6785807 Interleukin-4 and Interleukin-13 signaling
    R-HSA-6804757 Regulation of TP53 Degradation
    R-HSA-6804758 Regulation of TP53 Activity through Acetylation
    R-HSA-6804759 Regulation of TP53 Activity through Association with Co-factors
    R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
    R-HSA-69202 Cyclin E associated events during G1/S transition
    R-HSA-69656 Cyclin A:Cdk2-associated events at S phase entry
    R-HSA-8849469 PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1
    R-HSA-8876198 RAB GEFs exchange GTP for GDP on RABs
    R-HSA-8941332 RUNX2 regulates genes involved in cell migration
    R-HSA-8948751 Regulation of PTEN stability and activity
    R-HSA-9604323 Negative regulation of NOTCH4 signaling
    SABIO-RKiP31749
    SignaLinkiP31749
    SIGNORiP31749

    Miscellaneous databases

    ChiTaRSiAKT1 human
    EvolutionaryTraceiP31749
    GeneWikiiAKT1
    GenomeRNAii207
    PMAP-CutDBiP31749
    PROiPR:P31749
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000142208 Expressed in 215 organ(s), highest expression level in left adrenal gland
    CleanExiHS_AKT1
    ExpressionAtlasiP31749 baseline and differential
    GenevisibleiP31749 HS

    Family and domain databases

    CDDicd01241 PH_PKB, 1 hit
    cd05594 STKc_PKB_alpha, 1 hit
    Gene3Di2.30.29.30, 1 hit
    InterProiView protein in InterPro
    IPR000961 AGC-kinase_C
    IPR034676 Akt1
    IPR011009 Kinase-like_dom_sf
    IPR011993 PH-like_dom_sf
    IPR001849 PH_domain
    IPR039026 PH_PKB
    IPR017892 Pkinase_C
    IPR000719 Prot_kinase_dom
    IPR017441 Protein_kinase_ATP_BS
    IPR039027 RAC_alpha/beta
    IPR008271 Ser/Thr_kinase_AS
    PANTHERiPTHR24356:SF176 PTHR24356:SF176, 1 hit
    PfamiView protein in Pfam
    PF00169 PH, 1 hit
    PF00069 Pkinase, 1 hit
    PF00433 Pkinase_C, 1 hit
    SMARTiView protein in SMART
    SM00233 PH, 1 hit
    SM00133 S_TK_X, 1 hit
    SM00220 S_TKc, 1 hit
    SUPFAMiSSF56112 SSF56112, 1 hit
    PROSITEiView protein in PROSITE
    PS51285 AGC_KINASE_CTER, 1 hit
    PS50003 PH_DOMAIN, 1 hit
    PS00107 PROTEIN_KINASE_ATP, 1 hit
    PS50011 PROTEIN_KINASE_DOM, 1 hit
    PS00108 PROTEIN_KINASE_ST, 1 hit
    ProtoNetiSearch...

    Entry informationi

    Entry nameiAKT1_HUMAN
    AccessioniPrimary (citable) accession number: P31749
    Secondary accession number(s): B2RAM5, B7Z5R1, Q9BWB6
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 1, 1993
    Last sequence update: February 1, 2005
    Last modified: November 7, 2018
    This is version 230 of the entry and version 2 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Human chromosome 14
      Human chromosome 14: entries, gene names and cross-references to MIM
    7. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
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