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UniProtKB - Q9Y243 (AKT3_HUMAN)

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Protein

RAC-gamma serine/threonine-protein kinase

Gene

AKT3

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

Functioni

AKT3 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. AKT3 is the least studied AKT isoform. It plays an important role in brain development and is crucial for the viability of malignant glioma cells. AKT3 isoform may also be the key molecule in up-regulation and down-regulation of MMP13 via IL13. Required for the coordination of mitochondrial biogenesis with growth factor-induced increases in cellular energy demands. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis.2 Publications

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.

Enzyme regulationi

Two specific sites, one in the kinase domain (Thr-305) and the other in the C-terminal regulatory region (Ser-472), need to be phosphorylated for its full activation (By similarity). IGF-1 leads to the activation of AKT3, which may play a role in regulating cell survival.By similarity

Kineticsi

  1. KM=87.9 µM for ATP (for purified and in vitro activated AKT3)1 Publication
  2. KM=12.4 µM for peptide substrate (for purified and in vitro activated AKT3)1 Publication
  3. KM=118.7 µM for ATP (for recombinant myristoylated AKT3 expressed and immunoprecipitated from Rat-1 cells)1 Publication
  4. KM=2.3 µM for peptide substrate (for recombinant myristoylated AKT3 expressed and immunoprecipitated from Rat-1 cells)1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei177ATPPROSITE-ProRule annotation1
    Active sitei271Proton acceptorPROSITE-ProRule annotation1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi154 – 162ATPPROSITE-ProRule annotation9

    GO - Molecular functioni

    • ATP binding Source: UniProtKB
    • protein kinase activity Source: ProtInc
    • protein serine/threonine kinase activity Source: UniProtKB
    View the complete GO annotation on QuickGO ...

    GO - Biological processi

    • brain morphogenesis Source: Ensembl
    • homeostasis of number of cells within a tissue Source: Ensembl
    • intracellular signal transduction Source: GO_Central
    • mitochondrial genome maintenance Source: UniProtKB
    • negative regulation of cellular senescence Source: BHF-UCL
    • peptidyl-serine phosphorylation Source: GO_Central
    • positive regulation of artery morphogenesis Source: Ensembl
    • positive regulation of blood vessel endothelial cell migration Source: BHF-UCL
    • positive regulation of cell migration involved in sprouting angiogenesis Source: BHF-UCL
    • positive regulation of cell size Source: Ensembl
    • positive regulation of endothelial cell proliferation Source: BHF-UCL
    • positive regulation of TOR signaling Source: Ensembl
    • positive regulation of vascular endothelial cell proliferation Source: BHF-UCL
    • protein phosphorylation Source: ProtInc
    • signal transduction Source: UniProtKB
    View the complete GO annotation on QuickGO ...

    Keywordsi

    Molecular functionKinase, Serine/threonine-protein kinase, Transferase
    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-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-211163 AKT-mediated inactivation of FOXO1A
    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-5218920 VEGFR2 mediated vascular permeability
    R-HSA-5628897 TP53 Regulates Metabolic Genes
    R-HSA-5674400 Constitutive Signaling by AKT1 E17K in Cancer
    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-69202 Cyclin E associated events during G1/S transition
    R-HSA-69656 Cyclin A:Cdk2-associated events at S phase entry
    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
    SABIO-RKiQ9Y243
    SignaLinkiQ9Y243
    SIGNORiQ9Y243

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    RAC-gamma serine/threonine-protein kinase (EC:2.7.11.1)
    Alternative name(s):
    Protein kinase Akt-3
    Protein kinase B gamma
    Short name:
    PKB gamma
    RAC-PK-gamma
    STK-2
    Gene namesi
    Name:AKT3
    Synonyms:PKBG
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
    Proteomesi
    • UP000005640 Componenti: Chromosome 1

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000117020.16
    HGNCiHGNC:393 AKT3
    MIMi611223 gene
    neXtProtiNX_Q9Y243

    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

    Cytoplasm, Membrane, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    AKT3 is a key modulator of several tumors like melanoma, glioma and ovarian cancer. Active AKT3 increases progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Promotes melanoma tumorigenesis by decreasing apoptosis. Plays a key role in the genesis of ovarian cancers through modulation of G2/M phase transition. With AKT2, plays a pivotal role in the biology of glioblastoma.
    Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (MPPH2)4 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA syndrome characterized by megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome.
    See also OMIM:615937
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_069260229N → S in MPPH2. 2 PublicationsCorresponds to variant dbSNP:rs397514605EnsemblClinVar.1
    Natural variantiVAR_069261465R → W in MPPH2; disease phenotype overlaps with megalencephaly-capillary malformation syndrome. 1 PublicationCorresponds to variant dbSNP:rs587776935EnsemblClinVar.1

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi305T → A: No activation after pervanadate treatment. 1 Publication1
    Mutagenesisi305T → D: 2-fold increase of phosphorylation steady state level, no activation after pervanadate treatment. 1 Publication1
    Mutagenesisi447T → A: No effect. 1 Publication1
    Mutagenesisi447T → D: No effect. 1 Publication1
    Mutagenesisi472S → A: 67% decrease of activity after pervanadate treatment. 1 Publication1
    Mutagenesisi472S → D: 1.4-fold increase of phosphorylation steady state level, 50% decrease of activity after pervanadate treatment. 1 Publication1

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    DisGeNETi10000
    MalaCardsiAKT3
    MIMi615937 phenotype
    OpenTargetsiENSG00000117020
    Orphaneti99802 Hemimegalencephaly
    83473 Megalencephaly - polymicrogyria - postaxial polydactyly - hydrocephalus
    PharmGKBiPA24686

    Chemistry databases

    ChEMBLiCHEMBL4816
    GuidetoPHARMACOLOGYi2286

    Polymorphism and mutation databases

    BioMutaiAKT3
    DMDMi12643943

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Initiator methionineiRemovedCombined sources
    ChainiPRO_00000856112 – 479RAC-gamma serine/threonine-protein kinaseAdd BLAST478

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei2N-acetylserineCombined sources1
    Disulfide bondi59 ↔ 76By similarity
    Disulfide bondi293 ↔ 307By similarity
    Glycosylationi302O-linked (GlcNAc) threonineBy similarity1
    Modified residuei305Phosphothreonine; by PDPK11 Publication1
    Glycosylationi309O-linked (GlcNAc) threonineBy similarity1
    Modified residuei447PhosphothreonineCombined sources1
    Modified residuei472Phosphoserine; by PKC/PRKCZ1 Publication1

    Post-translational modificationi

    Phosphorylation on Thr-305 and Ser-472 is required for full activity.By similarity
    Ubiquitinated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome.3 Publications
    O-GlcNAcylation at Thr-302 and Thr-309 inhibits activating phosphorylation at Thr-305 via disrupting the interaction between AKT and PDK1.By similarity

    Keywords - PTMi

    Acetylation, Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

    Proteomic databases

    EPDiQ9Y243
    PaxDbiQ9Y243
    PeptideAtlasiQ9Y243
    PRIDEiQ9Y243
    ProteomicsDBi85641
    85642 [Q9Y243-2]

    PTM databases

    iPTMnetiQ9Y243
    PhosphoSitePlusiQ9Y243

    Expressioni

    Tissue specificityi

    In adult tissues, it is highly expressed in brain, lung and kidney, but weakly in heart, testis and liver. In fetal tissues, it is highly expressed in heart, liver and brain and not at all in kidney.

    Gene expression databases

    BgeeiENSG00000117020
    CleanExiHS_AKT3
    ExpressionAtlasiQ9Y243 baseline and differential
    GenevisibleiQ9Y243 HS

    Organism-specific databases

    HPAiCAB013090
    HPA026441

    Interactioni

    Subunit structurei

    Interacts (via PH domain) with TCL1A; this enhances AKT3 phosphorylation and activation. Interacts with TRAF6. Interacts with KCTD20 (By similarity). Interacts with BTBD10 (By similarity).By similarity3 Publications

    Binary interactionsi

    Show more details

    Protein-protein interaction databases

    BioGridi115318, 27 interactors
    DIPiDIP-32584N
    IntActiQ9Y243, 8 interactors
    MINTiQ9Y243
    STRINGi9606.ENSP00000263826

    Chemistry databases

    BindingDBiQ9Y243

    Structurei

    Secondary structure

    1479
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi6 – 15Combined sources10
    Beta strandi17 – 30Combined sources14
    Beta strandi33 – 41Combined sources9
    Helixi44 – 46Combined sources3
    Beta strandi51 – 55Combined sources5
    Beta strandi60 – 64Combined sources5
    Beta strandi66 – 68Combined sources3
    Beta strandi71 – 75Combined sources5
    Turni80 – 82Combined sources3
    Beta strandi84 – 88Combined sources5
    Helixi92 – 113Combined sources22

    3D structure databases

    ProteinModelPortaliQ9Y243
    SMRiQ9Y243
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini5 – 107PHPROSITE-ProRule annotationAdd BLAST103
    Domaini148 – 405Protein kinasePROSITE-ProRule annotationAdd BLAST258
    Domaini406 – 479AGC-kinase C-terminalAdd BLAST74

    Domaini

    Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PI3K) results in its targeting to the plasma membrane.

    Sequence similaritiesi

    Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.Curated

    Phylogenomic databases

    eggNOGiKOG0598 Eukaryota
    ENOG410XNPH LUCA
    GeneTreeiENSGT00920000148938
    HOGENOMiHOG000233033
    HOVERGENiHBG108317
    InParanoidiQ9Y243
    KOiK04456
    OMAiCQIMSVD
    OrthoDBiEOG091G06FF
    PhylomeDBiQ9Y243
    TreeFamiTF102004

    Family and domain databases

    CDDicd01241 PH_PKB, 1 hit
    cd05593 STKc_PKB_gamma, 1 hit
    Gene3Di2.30.29.30, 1 hit
    InterProiView protein in InterPro
    IPR000961 AGC-kinase_C
    IPR034675 Akt3
    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
    IPR039029 RAC_gamma-like
    IPR008271 Ser/Thr_kinase_AS
    PANTHERiPTHR24356:SF190 PTHR24356:SF190, 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.

    Sequence processingi: The displayed sequence is further processed into a mature form.

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

    Isoform 1 (identifier: Q9Y243-1) [UniParc]FASTAAdd to basket
    Also known as: PKB gamma

    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
    MSDVTIVKEG WVQKRGEYIK NWRPRYFLLK TDGSFIGYKE KPQDVDLPYP 
            60         70         80         90        100
    LNNFSVAKCQ LMKTERPKPN TFIIRCLQWT TVIERTFHVD TPEEREEWTE 
           110        120        130        140        150
    AIQAVADRLQ RQEEERMNCS PTSQIDNIGE EEMDASTTHH KRKTMNDFDY 
           160        170        180        190        200
    LKLLGKGTFG KVILVREKAS GKYYAMKILK KEVIIAKDEV AHTLTESRVL 
           210        220        230        240        250
    KNTRHPFLTS LKYSFQTKDR LCFVMEYVNG GELFFHLSRE RVFSEDRTRF 
           260        270        280        290        300
    YGAEIVSALD YLHSGKIVYR DLKLENLMLD KDGHIKITDF GLCKEGITDA 
           310        320        330        340        350
    ATMKTFCGTP EYLAPEVLED NDYGRAVDWW GLGVVMYEMM CGRLPFYNQD 
           360        370        380        390        400
    HEKLFELILM EDIKFPRTLS SDAKSLLSGL LIKDPNKRLG GGPDDAKEIM 
           410        420        430        440        450
    RHSFFSGVNW QDVYDKKLVP PFKPQVTSET DTRYFDEEFT AQTITITPPE 
           460        470 
    KYDEDGMDCM DNERRPHFPQ FSYSASGRE
    Length:479
    Mass (Da):55,775
    Last modified:November 1, 1999 - v1
    Checksum:iF08BDDE6502E78FB
    GO
    Isoform 2 (identifier: Q9Y243-2) [UniParc]FASTAAdd to basket
    Also known as: PKB gamma 1

    The sequence of this isoform differs from the canonical sequence as follows:
         452-479: YDEDGMDCMDNERRPHFPQFSYSASGRE → CQQSDCGMLGNWKK

    Show »
    Length:465
    Mass (Da):54,032
    Checksum:i592EF88B6937D1E0
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti279L → R in AAI21155 (PubMed:15489334).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_06583017E → K in MPPH2 and melanoma; results in activation of AKT. 3 PublicationsCorresponds to variant dbSNP:rs397514606EnsemblClinVar.1
    Natural variantiVAR_040358171G → R in a glioblastoma multiforme sample; somatic mutation. 1 Publication1
    Natural variantiVAR_069260229N → S in MPPH2. 2 PublicationsCorresponds to variant dbSNP:rs397514605EnsemblClinVar.1
    Natural variantiVAR_069261465R → W in MPPH2; disease phenotype overlaps with megalencephaly-capillary malformation syndrome. 1 PublicationCorresponds to variant dbSNP:rs587776935EnsemblClinVar.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_004947452 – 479YDEDG…ASGRE → CQQSDCGMLGNWKK in isoform 2. 3 PublicationsAdd BLAST28

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    		AF124141 mRNA Translation: AAD29089.1
    AF135794 mRNA Translation: AAD24196.1
    AF085234 mRNA Translation: AAL40392.1
    AJ245709 mRNA Translation: CAB53537.1
    AL117525 mRNA Translation: CAB55977.1 Different termination.
    AY005799 mRNA Translation: AAF91073.1
    AC096539 Genomic DNA No translation available.
    AL591721 Genomic DNA No translation available.
    AL592151 Genomic DNA No translation available.
    AL662889 Genomic DNA No translation available.
    CH471148 Genomic DNA Translation: EAW77093.1
    CH471148 Genomic DNA Translation: EAW77094.1
    BC121154 mRNA Translation: AAI21155.1
    CCDSiCCDS31076.1 [Q9Y243-2]
    CCDS31077.1 [Q9Y243-1]
    PIRiA59380
    T17287
    RefSeqiNP_001193658.1, NM_001206729.1 [Q9Y243-2]
    NP_005456.1, NM_005465.4 [Q9Y243-1]
    NP_859029.1, NM_181690.2 [Q9Y243-2]
    XP_005273051.1, XM_005272994.4 [Q9Y243-1]
    XP_005273052.1, XM_005272995.2 [Q9Y243-1]
    UniGeneiHs.498292

    Genome annotation databases

    EnsembliENST00000263826; ENSP00000263826; ENSG00000117020 [Q9Y243-1]
    ENST00000336199; ENSP00000336943; ENSG00000117020 [Q9Y243-2]
    ENST00000366539; ENSP00000355497; ENSG00000117020 [Q9Y243-1]
    ENST00000366540; ENSP00000355498; ENSG00000117020 [Q9Y243-2]
    ENST00000613395; ENSP00000479922; ENSG00000275199 [Q9Y243-2]
    ENST00000619536; ENSP00000483054; ENSG00000275199 [Q9Y243-2]
    ENST00000621586; ENSP00000479081; ENSG00000275199 [Q9Y243-1]
    GeneIDi10000
    KEGGihsa:10000
    UCSCiuc001hzz.2 human [Q9Y243-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiAKT3_HUMAN
    AccessioniPrimary (citable) accession number: Q9Y243
    Secondary accession number(s): Q0VAA6
    , Q5VTI1, Q5VTI2, Q96QV3, Q9UFP5
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 1, 2000
    Last sequence update: November 1, 1999
    Last modified: July 18, 2018
    This is version 194 of the entry and version 1 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. Human chromosome 1
      Human chromosome 1: entries, gene names and cross-references to MIM
    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 and mouse protein kinases
      Human and mouse protein kinases: classification and index
    7. SIMILARITY comments
      Index of protein domains and families

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