AKT1 and AKT2 are 2 putative cellular homologs of the v-akt oncogene of the retrovirus AKT8.
Cheng et al. (1992) reported the cDNA cloning, sequence analysis, and chromosome mapping of AKT2 and demonstrated
that this putative oncogene encodes a protein belonging to a subfamily of serine/threonine kinases containing SH2-like (Src
homology 2-like) domains.
NCBI Summary:
This gene is a putative oncogene encoding a protein belonging to a subfamily of serine/threonine kinases containing SH2-like (Src homology 2-like) domains, which is involved in signaling pathways. The gene serves as an oncogene in the tumorigenesis of cancer cells For example, its overexpression contributes to the malignant phenotype of a subset of human ductal pancreatic cancers. The encoded protein is a general protein kinase capable of phophorylating several known proteins, and has also been implicated in insulin signaling. [provided by RefSeq, Nov 2019]
Bellacosa A, et al reported the molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas.
,
The AKT2 gene is one of the human homologues of v-akt, the transduced oncogene
of the AKT8 virus, which induces lymphomas in mice. The authors conducted
a large-scale, multicenter study of AKT2 alterations in ovarian and breast cancer.
Southern-blot analysis demonstrated AKT2 amplification in 16 of 132 (12.1%)
ovarian carcinomas and in 3 of 106 (2.8%) breast carcinomas. No AKT2
alteration was detected in 24 benign or borderline tumors. Northern-blot analysis
revealed overexpression of AKT2 in 3 of 25 fresh ovarian carcinomas which
were negative for AKT2 amplification. The difference in the incidence of AKT2
alterations in ovarian and breast cancer suggests a specific role for this gene in
ovarian oncogenesis. Ovarian cancer patients with AKT2 alterations appear to have a
poor prognosis. Amplification of AKT2 was especially frequent in
undifferentiated tumors (4 of 8, p = 0.019), suggesting that AKT2 alterations may
be associated with tumor aggressiveness.
Expression regulated by
Growth Factors/ cytokines
Comment
Three members have been identified in the protein kinase B (PKB) family, i.e.,
Akt/PKB alpha, AKT2/PKB beta, and AKT3/PKB gamma. Previous studies have
demonstrated that only AKT2 is predominantly involved in human malignancies
and has oncogenic activity. However, the mechanism of transforming activity of
AKT2 is still not well understood. Liu AX, et al 1998 demonstrate the activation of AKT2
with several growth factors, including epidermal growth factor, insulin-like
growth factor 1, insulin-like growth factor II, basic fibroblast growth factor,
platelet-derived growth factor, and insulin, in human ovarian epithelial cancer
cells. The kinase activity and the phosphorylation of AKT2 were induced by the
growth factors and blocked by the phosphatidylinositol (PI) 3-kinase inhibitor,
wortmannin, and dominant-negative Ras (N17Ras). Moreover, the activated Ras
and v-Src, two proteins that transduce growth factor-generated signals, also
activated AKT2, and this activation was not significantly enhanced by growth
factor stimulation but was abrogated by wortmannin. These results indicate that
AKT2 is a downstream target of PI 3-kinase and that Ras and Src function
upstream of PI 3-kinase and mediate the activation of AKT2 by growth factors.
Ovarian localization
Surface epithelium
Comment
Follicle stages
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
2 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: AKT2: First Evidence of Genetic Association with Polycystic Ovary Syndrome. Goodarzi MO et al. Objective: Insulin resistance has been reported in up to 70% of women with polycystic ovary syndrome (PCOS). Physiologic and genetic data currently implicate post-insulin receptor signaling defects in substrates such as GSK3beta . The AKT2 gene was chosen as a candidate for PCOS because its product affects glucose metabolism and mitogenic signaling, interacts with GSK3beta, and mediates cell survival in the ovary. Research Design and Methods: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the surrounding community. 287 White women with PCOS and 187 White controls were genotyped for 4 SNPs in AKT2. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles. Single nucleotide polymorphisms (SNPs) and haplotypes were tested for association with PCOS risk and phenotypic markers of PCOS. Results: Minor allele carriers of SNPs rs3730051 and rs8100018 had increased odds of PCOS (OR=2.2, p=0.004 and OR=2.4, p=0.001, respectively). The haplotype T-G-C-T was significantly associated with PCOS (OR=2.0, p=0.01). Carriers of the risk haplotypes for both AKT2 and GSK3B had a further increased odds of PCOS (OR=3.1, p=0.005). Conclusions: These data suggest that polymorphisms in two components of the insulin signaling pathway, AKT2 and GSK3B, are associated with PCOS. Presence of multiple lesions in a single pathway may confer increased risk.
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Loss of PKB/Akt2 predisposes mice to ovarian cyst formation and increases the severity of polycystic ovary formation in vivo. Restuccia DF et al. Ovarian cysts affect women of all ages and decrease fertility. In particular, polycystic ovarian syndrome (PCOS), with multiple follicular cysts, affects 5-10% of women of reproductive age and can result in infertility. Current non-invasive treatments for PCOS can resolve cysts and restore fertility, but unresponsive patients must undergo severe ovarian wedge resection and resort to in vitro fertilization. PCOS is related to the deregulation of leutinizing hormone (LH) signaling at various levels of the hypothalamic-pituitary-ovarian axis and resultant hyper-production of androgens. As insulin resistance and compensatory hyperinsulemia are observed in 50-70% of PCOS patients, deregulated insulin signaling in the ovary is considered an important factor in the disease. Here we report that aged mice, specifically lacking the PKB/AKT2 isoform that is crucial for insulin signaling, develop increased testosterone levels and ovarian cysts also observed in insulin resistant PCOS patients. Young PKB/AKT2 knockout mice subjected to a mouse model of PCOS, by treatment with LH, exhibited a cyst area threefold greater than controls, but without hyperinsulemia. Thus, loss of PKB/AKT2 may predispose mice to ovarian cysts independent of hyperactive insulin signaling. Targeted therapeutic augmentation of specific PKB/AKT2 signaling may therefore provide a new avenue for the treatment and management of ovarian cysts.