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RAC-gamma serine/threonine protein kinase; protein kinase Akt-3; protein kinase B gamma; PKB gamma; RAC-PK-gamma; STK-2 (AKT3, PKBG)
Function:
- AKT3 is one of 3 AKT kinases (AKT1, AKT2 & AKT3), that regulate many processes including metabolism, proliferation, cell survival, growth & angiogenesis
- AKT3 is the least studied AKT isoform
- role in brain development AKT3 isoform may also be the key molecule in up-regulation & 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 siRNA reduces expression of phosphorylated BAD, resulting in induction of caspase-dependent apoptosis
- two specific sites, one in the kinase domain (Thr-305) & the other in the C-terminal regulatory region (Ser-472), need to be phosphorylated for its full activation
- phosphorylated upon DNA damage, probably by ATM or ATR
- ubiquitinated
- when fully phosphorylated & translocated into the nucleus, undergoes Lys-48-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome
- interacts (via PH domain) with TCL1A
- interaction enhances AKT3 phosphorylation & activation
- interacts with TRAF6
- IGF-1 leads to the activation of AKT3, which may play a role in regulating cell survival
Kinetic parameters:
- KM=87.9 uM for ATP (for purified & in vitro activated AKT3)
- KM=12.4 uM for peptide substrate (for purified & in vitro activated AKT3)
- KM=118.7 uM for ATP (for recombinant myristoylated AKT3 expressed & immunoprecipitated from Rat-1 cells)
- KM=2.3 uM for peptide substrate (for recombinant myristoylated AKT3 expressed & immunoprecipitated from Rat-1 cells)
Structure:
- binding of the PH domain to phosphatidylinositol-3-kinase alpha (PI(3)K) results in its targeting to the plasma membrane
- belongs to the protein kinase superfamily, AGC Ser/Thr protein kinase family, RAC subfamily
- contains 1 AGC-kinase C-terminal domain
- contains 1 PH domain
- contains 1 protein kinase domain
Compartment:
- nucleus, cytoplasm, peripheral membrane
- membrane-associated after cell stimulation
Alternative splicing: named isoforms=2
Expression:
- adult tissues
- highly expressed in brain, lung & kidney
- weakly in heart, testis & liver
- fetal tissues
- highly expressed in heart, liver & brain
- not expressed in kidney
Pathology:
- AKT3 is a key modulator of several tumors including
a) melanoma
1] active AKT3 increases progressively during melanoma progression
2] highest levels present in advanced-stage metastatic melanomas
3] promotes melanoma tumorigenesis by decreasing apoptosis
b) glioma
1] essential for viability of malignant glioma cells
2] with AKT2, plays a role in glioblastoma
c) ovarian cancer
- role in the genesis of ovarian cancers through modulation of G2/M phase transition
General
nuclear protein
rac S/T kinase; AKT kinase
Properties
SIZE: entity length = 479 aa
MW = 56 kD
COMPARTMENT: cytoplasm
cell nucleus
MOTIF: PH domain {5-107}
MOTIF: cysteine residue {C59}
MODIFICATION: cysteine residue {C76}
cysteine residue {C76}
MODIFICATION: cysteine residue {C59}
Ser phosphorylation site {S120}
Ser phosphorylation site {S123}
kinase domain
SITE: 148-405
MOTIF: ATP-binding site
NAME: ATP-binding site
SITE: 154-162
ATP-binding site
NAME: ATP-binding site
SITE: 177-177
aspartate residue {D271}
cysteine residue {C293}
MODIFICATION: cysteine residue {C307}
Thr phosphorylation site {T305}
cysteine residue {C307}
MODIFICATION: cysteine residue {C293}
AGC-kinase C-terminal {406-479}
MOTIF: Ser phosphorylation site {S472}
STATE: active state
Database Correlations
OMIM 611223
UniProt Q9Y243
PFAM correlations
Entrez Gene 10000
Kegg hsa:10000
ENZYME 2.7.11.1
References
- UniProt :accession Q9Y243
- Atlas of Genetics & Cytogenetics in Oncology & Haematology
http://atlasgeneticsoncology.org/genes/AKT3ID615ch1q44.html