Q9WUA6 (AKT3_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 131. History...
Names and origin
|Protein names||Recommended name:|
RAC-gamma serine/threonine-protein kinase
Protein kinase Akt-3
Protein kinase B gamma
Short name=PKB gamma
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||479 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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 specificityhas 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 mayalso 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. Ref.3 Ref.5
ATP + a protein = ADP + a phosphoprotein.
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.
Interacts (via PH domain) with TCL1A; this enhances AKT3 phosphorylation and activation. Interacts with TRAF6 By similarity.
Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PI3K) results in its targeting to the plasma membrane.
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.
O-GlcNAcylation at Thr-302 and Thr-309 inhibits activating phosphorylation at Thr-305 via disrupting the interaction between AKT and PDK1 By similarity.
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. Ref.4
Contains 1 AGC-kinase C-terminal domain.
Contains 1 PH domain.
Contains 1 protein kinase domain.
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 specificfunctions 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.
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: Q9WUA6-1) |
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.
|Isoform 2 (identifier: Q9WUA6-2) |
Also known as: PKB gamma 1;
The sequence of this isoform differs from the canonical sequence as follows:
452-479: YDDDGMDGMDNERRPHFPQFSYSASGRE → CQQSDCGMLGNWKKNDNKK
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed By similarity|
|Chain||2 – 479||478||RAC-gamma serine/threonine-protein kinase||PRO_0000085612|
|Domain||5 – 107||103||PH|
|Domain||148 – 405||258||Protein kinase|
|Domain||406 – 479||74||AGC-kinase C-terminal|
|Nucleotide binding||154 – 162||9||ATP By similarity|
|Active site||271||1||Proton acceptor By similarity|
|Binding site||177||1||ATP By similarity|
Amino acid modifications
|Modified residue||2||1||N-acetylserine By similarity|
|Modified residue||305||1||Phosphothreonine; by PDPK1 By similarity|
|Modified residue||472||1||Phosphoserine; by PKC/PRKCZ By similarity|
|Glycosylation||302||1||O-linked (GlcNAc) By similarity|
|Glycosylation||309||1||O-linked (GlcNAc) By similarity|
|Disulfide bond||59 ↔ 76||By similarity|
|Disulfide bond||293 ↔ 307||By similarity|
|Alternative sequence||452 – 479||28||YDDDG…ASGRE → CQQSDCGMLGNWKKNDNKK in isoform 2.||VSP_004948|
|Mutagenesis||219||1||D → 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. Ref.5|
|||"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].
|||"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).
|||"Role for Akt3/protein kinase Bgamma in attainment of normal brain size."|
Easton R.M., Cho H., Roovers K., Shineman D.W., Mizrahi M., Forman M.S., Lee V.M., Szabolcs M., de Jong R., Oltersdorf T., Ludwig T., Efstratiadis A., Birnbaum M.J.
Mol. Cell. Biol. 25:1869-1878(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"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.
|||"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.
|||"Akt signalling in health and disease."|
Hers I., Vincent E.E., Tavare J.M.
Cell. Signal. 23:1515-1527(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
|+||Additional computationally mapped references.|
|AF124142 mRNA. Translation: AAD29090.1.|
|RefSeq||NP_035915.3. NM_011785.3. |
3D structure databases
|SMR||Q9WUA6. Positions 3-476. |
Protein-protein interaction databases
|BioGrid||204720. 2 interactions.|
|IntAct||Q9WUA6. 1 interaction.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000019843; ENSMUSP00000019843; ENSMUSG00000019699. [Q9WUA6-2]|
ENSMUST00000111159; ENSMUSP00000106789; ENSMUSG00000019699. [Q9WUA6-1]
ENSMUST00000111160; ENSMUSP00000106790; ENSMUSG00000019699. [Q9WUA6-1]
|UCSC||uc007duk.2. mouse. [Q9WUA6-1]|
|MGI||MGI:1345147. Akt3. |
Enzyme and pathway databases
|BRENDA||18.104.22.168. 3474. |
Gene expression databases
Family and domain databases
|Gene3D||22.214.171.124. 1 hit. |
|InterPro||IPR000961. AGC-kinase_C. |
|Pfam||PF00169. PH. 1 hit. |
PF00069. Pkinase. 1 hit.
PF00433. Pkinase_C. 1 hit.
|SMART||SM00233. PH. 1 hit. |
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|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.
|Accession||Primary (citable) accession number: Q9WUA6|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|