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Q9WUA6

- AKT3_MOUSE

UniProt

Q9WUA6 - AKT3_MOUSE

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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

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
Complete GO annotation...

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-KW
  3. plasma membrane Source: Ensembl
Complete GO annotation...

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). Interacts with KCTD20 (PubMed:24156551). Interacts with BTBD10 (PubMed:18160256).By similarity2 Publications

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.
GeneTreeiENSGT00770000120449.
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.
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

        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
KYDDDGMDGM DNERRPHFPQ FSYSASGRE
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:
EMBLi
GenBanki
DDBJi
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:
EMBLi
GenBanki
DDBJi
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 ENSGT00770000120449.
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

ChiTaRSi Akt3. mouse.
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.
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. "A novel Akt/PKB-interacting protein promotes cell adhesion and inhibits familial amyotrophic lateral sclerosis-linked mutant SOD1-induced neuronal death via inhibition of PP2A-mediated dephosphorylation of Akt/PKB."
    Nawa M., Kanekura K., Hashimoto Y., Aiso S., Matsuoka M.
    Cell. Signal. 20:493-505(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH BTBD10.
  5. "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.
  6. "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.
  7. Cited for: REVIEW ON FUNCTION.
  8. "KCTD20, a relative of BTBD10, is a positive regulator of Akt."
    Nawa M., Matsuoka M.
    BMC Biochem. 14:27-27(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH KCTD20.

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: November 26, 2014
This is version 137 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