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
  • melanoma
    • active AKT3 increases progressively during melanoma progression
    • highest levels present in advanced-stage metastatic melanomas
    • promotes melanoma tumorigenesis by decreasing apoptosis
  • glioma
    • essential for viability of malignant glioma cells
    • with AKT2, plays a role in glioblastoma
  • ovarian cancer
    • role in the genesis of ovarian cancers through modulation of G2/M phase transition

More general terms

• rac S/T kinase; AKT kinase
• nuclear protein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=10000
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:10000
• OMIM: https://mirror.omim.org/entry/611223
• UniProt: http://www.uniprot.org/uniprot/Q9Y243.html