Cancer, endocrine disorders

Familial partial lipodystrophy due to Akt2 mutations; hypoinsulinemic hypoglycemia with hemihypertrophy (HIHGHH); Insulin resistance; Diabetes mellitus, Type 2; hemihypertrophy; Diabetes mellitus, noninsulin-dependent (NIDDM); hypertension, Insulin resistance-related

The R274H mutation in Akt2 is associated with non-insulin-dependent diabetes mellitus, which is a disorder of glucose homeostasis due to lack of recognition of the body's own insulin. R274 in Akt2 normally shields T308 in the activation loop against dephosphorylation, which allows Akt2 to remain catalytically active. Therefore, the R274H mutation is a loss of function mutation. The gain of function E17K mutation is linked to hypoinsulinemic hypoglycemia with hemihypertrophy. It is a disorder with hypoglycemia, low insulin levels, and low serum levels of ketone bodies and branched-chain amino acids, which may lead to reduced consciousness and hypoglycemic seizures. In Akt1, the equivalent E17K mutation leads to plamsa membrane accumulation, catalytic activation and induction of GLUT4 translocation, which induces glucose uptake.
 

Thymoma; ovarian epithelial cancer

AKT2 is a known concoprotein (OP). Cancer-related mutations in human tumours point to a gain of function of the protein kinase. The active form of the protein kinase normally acts to promote tumour cell proliferation. In many cancers, AKT2 is found to be overexpressed and amplified. It is also linked with invasion, cell migration and induction of angiogenesis. It is important in cell survival regulation, insulin signalling, angiogenesis and tumour formation. Defects in AKT2 contributes to suspectibility to breast cancer and the malignancy of a subset of human ductal pancreatic cancer. AKT2 promotes metastasis of tumour cells, but does not affect the latency of tumour development. It, together with AKT3, has a critical role in glioblastomas. There are no predominent mutations in AKT2 in human cancers, with a relatively dispersed pattern of low level mutations through out the full length of the protein.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Brain oligodendrogliomas (%CFC= -64, p<0.061); Cervical cancer stage 2B (%CFC= +122, p<0.052); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +1527, p<0.0001); and Ovary adenocarcinomas (%CFC= +81, p<0.003). The COSMIC website notes an up-regulated expression score for AKT2 in diverse human cancers of 798, which is 1.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 212 for this protein kinase in human cancers was 3.5-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.07 % in 26371 diverse cancer specimens. This rate is only -1 % lower and is very similar to the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.37 % in 1300 large intestine cancers tested; 0.27 % in 910 skin cancers tested; 0.16 % in 1941 lung cancers tested.

None >3 in 21,349 cancer specimens

Only 1 deletion, and no insertions or complex mutations are noted on the COSMIC website.