Disease relevance of AKT3

• Mutational Analysis of AKT1, AKT2 and AKT3 Genes in Common Human Carcinomas [1].
• These data suggest an important role for AKT3 in glioblastoma multiforme [2].
• Deregulated Akt3 activity promotes development of malignant melanoma [3].
• In a prostate cancer cell line lacking the tumor suppressor PTEN (a lipid and protein phosphatase), the basal enzymatic activity of Akt3 was constitutively elevated and represented the major active Akt in these cells [4].
• In the estrogen receptor-deficient breast cancer cells and the androgen-insensitive prostate cells, the amount of Akt3 enzymatic activity was approximately 20-60-fold higher than in the cells that were estrogen- or androgen-responsive [4].

High impact information on AKT3

• Activation of PI3K pathway components occurs by PTEN loss and by AKT3 amplification [5].
• The AKT1, AKT2, and AKT3 kinases have emerged as critical mediators of signal transduction pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase [6].
• Specific silencing of AKT3 using short hairpin RNA markedly inhibited proliferation of the two cell lines with highest AKT3 expression and total AKT activity, OVCA429 and DOV13, by slowing G(2)-M phase transition [7].
• A specific role for AKT3 in the genesis of ovarian cancer through modulation of G(2)-M phase transition [7].
• AKT2 showed the highest Km value for ATP, and AKT3 showed the highest kcat value [8].

Chemical compound and disease context of AKT3

• Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines [4].
• CONCLUSION: Taken together, these results suggest that specific Akt isoforms such as Akt2 and Akt3 might be involved in chemoresistance to cisplatin and that these isoforms could be putative targets for gene therapy in uterine cancers [9].

Biological context of AKT3

• Previous studies have demonstrated that AKT1 and AKT3 are activated by heat shock and oxidative stress via both phosphatidylinositol 3-kinase-dependent and -independent pathways [10].
• However, the reported sequence of the rat Akt3 protein differed significantly from this in that it lacked 25 amino acids in the C-terminal region, including this key regulatory serine phosphorylation site (Biochem. Biophys. Res. Commun. 216, 526-534) [11].
• We have also mapped the rodent homologs of AKT3 to rat chromosome 13q24-->q26 and mouse chromosome 1H4-6 by FISH [12].
• We have now cloned the human homolog of this cDNA, and we have used this clone to map the AKT3 gene to human chromosome 1q44 by fluorescence in situ hybridization (FISH) [12].
• We report that selective activation of the Akt3 protein promotes cell survival and tumor development in 43 to 60% of nonfamilial melanomas [3].

Anatomical context of AKT3

• It has been observed that the expression levels of AKT1, AKT2, and AKT3 vary, but the levels of phospho-Ser473 AKT and phospho-Thr308 AKT are quite unique in these cancer cell lines, and that CL-1 cells have the highest basal levels of AKT activation among these cell lines [13].
• Furthermore, upon insulin stimulation of transfected cells, PKB gamma 1 translocates to the plasma membrane to a lesser extent than PKB gamma [14].
• Akt1 was the predominant isoform expressed in chromaffin cells, although lower levels of Akt2 and Akt3 were also found [15].

Associations of AKT3 with chemical compounds

• In the present studies we show that the deduced sequence of human Akt3 contains this serine and that it is phosphorylated in response to insulin [11].
• Taken together, these results suggest that phosphorylation of the hydrophobic motif at the extreme C terminus of PKB gamma may facilitate translocation of the kinase to the membrane and/or its phosphorylation on the activation loop site by phosphoinositide-dependent protein kinase-1 [14].
• We have reported previously the cloning and characterization of human and mouse protein kinase B gamma (PKB gamma), the third member of the PKB family of second messenger-regulated serine/threonine kinases (Brodbeck, D., Cron, P., and Hemmings, B. A. (1999) J. Biol. Chem. 274, 9133--9136) [14].
• In vitro kinase assays using immunoprecipitation and anti-Akt1, -Akt2, and -Akt3-specific antibodies demonstrated that Akt1 is activated by estradiol in MCF-7 cells whereas Akt3 is the activated isoform in ER-negative MDA-MB231 cells, implying that selective activation of Akt subtypes plays a role in the actions of estradiol [16].
• Cisplatin induced apoptosis in HeLa and HEC-1-A cells, but KLE cells expressing Akt2 and Akt3 remained more resistant to cisplatin [9].

Regulatory relationships of AKT3

• These results indicate that human Akt3 is regulated similarly to Akt1 and Akt2 [11].
• Targeted reduction of Akt3 activity with siRNA or by expressing active PTEN protein stimulated apoptotic signaling, which reduced cell survival by increasing apoptosis rates thereby inhibiting melanoma tumor development [3].
• EGF-induced Akt3 activation was demonstrated by Ser-472 phosphorylation of Akt3 but in a restrictive fashion [17].

Other interactions of AKT3

• Neither compound inhibited Akt3 nor mutants lacking the PH (pleckstrin homology) domain at concentrations up to 250 microM [18].

Analytical, diagnostic and therapeutic context of AKT3

• To see if the increase in Akt3 could be due to chromosomal abnormalities, the Akt3 gene was assigned to human chromosome 1q44 by fluorescence in situ hybridization and radiation hybrid cell panel analyses [4].
• DNA gel blot analysis with pulsed-field gel electrophoresis showed that AKT1, AKT2, AKT3, and AKTR and their homologues are on a single chromosome [19].
• The isoforms AKT1 and AKT2 were expressed at the mRNA level in all cell lines, while no relevant AKT3 mRNA levels were detected by conventional and quantitative RT-PCR [20].

References