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Q9WUA6

- AKT3_MOUSE

UniProt

Q9WUA6 - AKT3_MOUSE

Protein

RAC-gamma serine/threonine-protein kinase

Gene

Akt3

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 135 (01 Oct 2014)
      Sequence version 1 (01 Nov 1999)
      Previous versions | rss
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    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

    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. IGF-1 leads to the activation of AKT3, which may play a role in regulating cell survival.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei177 – 1771ATPPROSITE-ProRule annotation
    Active sitei271 – 2711Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi154 – 1629ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. protein kinase activity Source: MGI
    3. protein serine/threonine kinase activity Source: UniProtKB-KW

    GO - Biological processi

    1. cellular response to insulin stimulus Source: MGI
    2. mitochondrial genome maintenance Source: Ensembl
    3. peptidyl-serine phosphorylation Source: MGI
    4. peptidyl-threonine phosphorylation Source: MGI
    5. signal transduction Source: Ensembl

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.11.1. 3474.

    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
    Gene namesi
    Name:Akt3
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 1

    Organism-specific databases

    MGIiMGI:1345147. Akt3.

    Subcellular locationi

    Nucleus By similarity. Cytoplasm. Membrane; Peripheral membrane protein
    Note: Membrane-associated after cell stimulation leading to its translocation.

    GO - Cellular componenti

    1. Golgi apparatus Source: Ensembl
    2. nucleus Source: UniProtKB-SubCell
    3. plasma membrane Source: Ensembl

    Keywords - Cellular componenti

    Cytoplasm, Membrane, Nucleus

    Pathology & Biotechi

    Disruption phenotypei

    Results in the cytoplasmic accumulation of the master regulator of mitochondrial biogenesis, Ppargc1a, and a reduction in known Ppargc1a target genes, which leads to an abnormal mitochondrial phenotype in the brain tissue.1 Publication

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi219 – 2191D → V: Enhances kinase activity and causes low seizure threshold, sporadic tonic-clonic seizures, brain enlargement and ectopic neurons in the dentate hilus and molecular layer of the hippocampus. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 479478RAC-gamma serine/threonine-protein kinasePRO_0000085612Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylserineBy similarity
    Disulfide bondi59 ↔ 76By similarity
    Disulfide bondi293 ↔ 307By similarity
    Glycosylationi302 – 3021O-linked (GlcNAc)By similarity
    Modified residuei305 – 3051Phosphothreonine; by PDPK1By similarity
    Glycosylationi309 – 3091O-linked (GlcNAc)By similarity
    Modified residuei472 – 4721Phosphoserine; by PKC/PRKCZBy similarity

    Post-translational modificationi

    Phosphorylation on Thr-305 and Ser-472 is required for full activity.
    Ubiquitinated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome By similarity.By similarity
    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

    MaxQBiQ9WUA6.
    PaxDbiQ9WUA6.
    PRIDEiQ9WUA6.

    PTM databases

    PhosphoSiteiQ9WUA6.

    Expressioni

    Tissue specificityi

    Isoform 1 is expressed in prostate, testis, uterus and mammary gland and isoform 2 is expressed in prostate, testis and mammary gland.

    Gene expression databases

    BgeeiQ9WUA6.
    CleanExiMM_AKT3.
    GenevestigatoriQ9WUA6.

    Interactioni

    Subunit structurei

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

    Protein-protein interaction databases

    BioGridi204720. 2 interactions.
    IntActiQ9WUA6. 1 interaction.
    MINTiMINT-4087479.
    STRINGi10090.ENSMUSP00000106790.

    Structurei

    3D structure databases

    ProteinModelPortaliQ9WUA6.
    SMRiQ9WUA6. Positions 3-476.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini5 – 107103PHPROSITE-ProRule annotationAdd
    BLAST
    Domaini148 – 405258Protein kinasePROSITE-ProRule annotationAdd
    BLAST
    Domaini406 – 47974AGC-kinase C-terminalAdd
    BLAST

    Domaini

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

    Sequence similaritiesi

    Contains 1 AGC-kinase C-terminal domain.Curated
    Contains 1 PH domain.PROSITE-ProRule annotation
    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00740000114960.
    HOGENOMiHOG000233033.
    HOVERGENiHBG108317.
    InParanoidiQ9WUA6.
    KOiK04456.
    OMAiMRHSFFA.
    OrthoDBiEOG7Q5HCW.
    PhylomeDBiQ9WUA6.
    TreeFamiTF102004.

    Family and domain databases

    Gene3Di2.30.29.30. 1 hit.
    InterProiIPR000961. AGC-kinase_C.
    IPR011009. Kinase-like_dom.
    IPR001849. PH_domain.
    IPR011993. PH_like_dom.
    IPR017892. Pkinase_C.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF00169. PH. 1 hit.
    PF00069. Pkinase. 1 hit.
    PF00433. Pkinase_C. 1 hit.
    [Graphical view]
    SMARTiSM00233. PH. 1 hit.
    SM00133. S_TK_X. 1 hit.
    SM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS51285. 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.
    [Graphical view]

    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. Align

    Isoform 1 (identifier: Q9WUA6-1) [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

    MSDVTIVKEG WVQKRGEYIK NWRPRYFLLK TDGSFIGYKE KPQDVDLPYP    50
    LNNFSVAKCQ LMKTERPKPN TFIIRCLQWT TVIERTFHVD TPEEREEWTE 100
    AIQAVADRLQ RQEEERMNCS PTSQIDNIGE EEMDASTTHH KRKTMNDFDY 150
    LKLLGKGTFG KVILVREKAS GKYYAMKILK KEVIIAKDEV AHTLTESRVL 200
    KNTRHPFLTS LKYSFQTKDR LCFVMEYVNG GELFFHLSRE RVFSEDRTRF 250
    YGAEIVSALD YLHSGKIVYR DLKLENLMLD KDGHIKITDF GLCKEGITDA 300
    ATMKTFCGTP EYLAPEVLED NDYGRAVDWW GLGVVMYEMM CGRLPFYNQD 350
    HEKLFELILM EDIKFPRTLS SDAKSLLSGL LIKDPNKRLG GGPDDAKEIM 400
    RHSFFSGVNW QDVYDKKLVP PFKPQVTSET DTRYFDEEFT AQTITITPPE 450
    KYDDDGMDGM DNERRPHFPQ FSYSASGRE 479
    Length:479
    Mass (Da):55,714
    Last modified:November 1, 1999 - v1
    Checksum:iF08ACDF75743B8FB
    GO
    Isoform 2 (identifier: Q9WUA6-2) [UniParc]FASTAAdd to Basket

    Also known as: PKB gamma 1

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

    Show »
    Length:470
    Mass (Da):54,631
    Checksum:iB4352DF496792EF8
    GO

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei452 – 47928YDDDG…ASGRE → CQQSDCGMLGNWKKNDNKK in isoform 2. 1 PublicationVSP_004948Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF124142 mRNA. Translation: AAD29090.1.
    CCDSiCCDS35799.1. [Q9WUA6-1]
    RefSeqiNP_035915.3. NM_011785.3. [Q9WUA6-1]
    XP_006496881.1. XM_006496818.1. [Q9WUA6-1]
    XP_006496882.1. XM_006496819.1. [Q9WUA6-1]
    UniGeneiMm.235194.

    Genome annotation databases

    EnsembliENSMUST00000019843; ENSMUSP00000019843; ENSMUSG00000019699. [Q9WUA6-2]
    ENSMUST00000111159; ENSMUSP00000106789; ENSMUSG00000019699. [Q9WUA6-1]
    ENSMUST00000111160; ENSMUSP00000106790; ENSMUSG00000019699. [Q9WUA6-1]
    GeneIDi23797.
    KEGGimmu:23797.
    UCSCiuc007duk.2. mouse. [Q9WUA6-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF124142 mRNA. Translation: AAD29090.1 .
    CCDSi CCDS35799.1. [Q9WUA6-1 ]
    RefSeqi NP_035915.3. NM_011785.3. [Q9WUA6-1 ]
    XP_006496881.1. XM_006496818.1. [Q9WUA6-1 ]
    XP_006496882.1. XM_006496819.1. [Q9WUA6-1 ]
    UniGenei Mm.235194.

    3D structure databases

    ProteinModelPortali Q9WUA6.
    SMRi Q9WUA6. Positions 3-476.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 204720. 2 interactions.
    IntActi Q9WUA6. 1 interaction.
    MINTi MINT-4087479.
    STRINGi 10090.ENSMUSP00000106790.

    PTM databases

    PhosphoSitei Q9WUA6.

    Proteomic databases

    MaxQBi Q9WUA6.
    PaxDbi Q9WUA6.
    PRIDEi Q9WUA6.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000019843 ; ENSMUSP00000019843 ; ENSMUSG00000019699 . [Q9WUA6-2 ]
    ENSMUST00000111159 ; ENSMUSP00000106789 ; ENSMUSG00000019699 . [Q9WUA6-1 ]
    ENSMUST00000111160 ; ENSMUSP00000106790 ; ENSMUSG00000019699 . [Q9WUA6-1 ]
    GeneIDi 23797.
    KEGGi mmu:23797.
    UCSCi uc007duk.2. mouse. [Q9WUA6-1 ]

    Organism-specific databases

    CTDi 10000.
    MGIi MGI:1345147. Akt3.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00740000114960.
    HOGENOMi HOG000233033.
    HOVERGENi HBG108317.
    InParanoidi Q9WUA6.
    KOi K04456.
    OMAi MRHSFFA.
    OrthoDBi EOG7Q5HCW.
    PhylomeDBi Q9WUA6.
    TreeFami TF102004.

    Enzyme and pathway databases

    BRENDAi 2.7.11.1. 3474.

    Miscellaneous databases

    NextBioi 303415.
    PROi Q9WUA6.
    SOURCEi Search...

    Gene expression databases

    Bgeei Q9WUA6.
    CleanExi MM_AKT3.
    Genevestigatori Q9WUA6.

    Family and domain databases

    Gene3Di 2.30.29.30. 1 hit.
    InterProi IPR000961. AGC-kinase_C.
    IPR011009. Kinase-like_dom.
    IPR001849. PH_domain.
    IPR011993. PH_like_dom.
    IPR017892. Pkinase_C.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view ]
    Pfami PF00169. PH. 1 hit.
    PF00069. Pkinase. 1 hit.
    PF00433. Pkinase_C. 1 hit.
    [Graphical view ]
    SMARTi SM00233. PH. 1 hit.
    SM00133. S_TK_X. 1 hit.
    SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi 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.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "A human protein kinase B gamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain."
      Brodbeck D., Cron P., Hemmings B.A.
      J. Biol. Chem. 274:9133-9136(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    2. "Two splice variants of PKB gamma have different regulatory capacity depending on the presence or absence of the regulatory phosphorylation site Ser-472 in the C-terminal hydrophobic domain."
      Brodbeck D., Hill M.M., Hemmings B.A.
      J. Biol. Chem. 276:29550-29558(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
      Tissue: Brain.
    3. Cited for: FUNCTION.
    4. "VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase."
      Wright G.L., Maroulakou I.G., Eldridge J., Liby T.L., Sridharan V., Tsichlis P.N., Muise-Helmericks R.C.
      FASEB J. 22:3264-3275(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE.
    5. "A novel Akt3 mutation associated with enhanced kinase activity and seizure susceptibility in mice."
      Tokuda S., Mahaffey C.L., Monks B., Faulkner C.R., Birnbaum M.J., Danzer S.C., Frankel W.N.
      Hum. Mol. Genet. 20:988-999(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: MUTAGENESIS OF ASP-219, FUNCTION.
    6. Cited for: REVIEW ON FUNCTION.

    Entry informationi

    Entry nameiAKT3_MOUSE
    AccessioniPrimary (citable) accession number: Q9WUA6
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 1, 2000
    Last sequence update: November 1, 1999
    Last modified: October 1, 2014
    This is version 135 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    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

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3