Alternative titles; symbols
HGNC Approved Gene Symbol: AKT2
SNOMEDCT: 44054006; ICD10CM: E11;
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38) : 19:40,230,317-40,285,345 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | Diabetes mellitus, type II | 125853 | Autosomal dominant | 3 |
| Hypoinsulinemic hypoglycemia with hemihypertrophy | 240900 | Autosomal dominant | 3 |
AKT2 encodes a protein belonging to a subfamily of serine/threonine kinases containing Src homology 2 (SH2)-like domains (Cheng et al., 1992).
Staal (1987) cloned AKT1 (164730) and AKT2, 2 putative cellular homologs of the v-akt oncogene of the retrovirus AKT8. Cheng et al. (1992) cloned AKT2 cDNA. The deduced 481-amino acid protein has a molecular mass of 56 kD. It shares sequence homology with serine/threonine kinases and contains an SH2-like domain.
Cheng et al. (1992) showed that AKT2 was amplified and overexpressed in 2 of 8 ovarian carcinoma cell lines and 2 of 15 primary ovarian tumors. Cheng et al. (1996) demonstrated that AKT2 is amplified in approximately 10% of pancreatic carcinomas. They found, furthermore, that expression of AKT2 protein was greatly decreased when pancreatic cancer cells were transfected with antisense AKT2. Furthermore, tumorigenicity in nude mice was markedly reduced in the pancreatic cancer cells expressing antisense AKT2 RNA. Cells expressing antisense AKT2 RNA remained confined in a xenotransplant assay, whereas the untransfected cells showed invasion of surrounding tissues. The data were interpreted as suggesting that overexpression of AKT2 contributes to the malignant phenotype of a subset of human ductal pancreatic cancers.
Li et al. (2007) described a mechanism by which insulin (176730), through the intermediary protein kinase AKT2/PKB-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator PGC1-alpha (604517), a global regulator of hepatic metabolism during fasting. Phosphorylation prevents the recruitment of PGC1-alpha to the cognate promoters, impairing its ability to promote gluconeogenesis and fatty acid oxidation. Li et al. (2007) concluded that their results defined a mechanism by which insulin controls lipid catabolism in the liver and suggested a novel site for therapy in type 2 diabetes mellitus (see 125853).
By fluorescence in situ hybridization (FISH), Cheng et al. (1992) mapped the AKT2 gene to 19q13.1-q13.2. In the 2 ovarian carcinoma cell lines exhibiting amplification of AKT2, the amplified sequences were located within homogeneously staining regions (HSR). In the FISH experiments, all signals on chromosome 19 were located at subband 19q13.1 or at the interface between subbands 19q13.1 and 19q13.2.
Altomare et al. (1996) mapped the murine homolog to mouse chromosome 7 in band B1. A pseudogene was mapped to proximal mouse chromosome 11.
Type 2 Diabetes Mellitus
In a 34-year-old female who had developed type 2 diabetes mellitus (T2D; 125853) at 30 years of age, George et al. (2004) identified a missense mutation altering the invariant arginine at codon 274 of AKT2, changing it to a histidine (R274H; 164731.0001). Arginine-274 (R274) forms part of an RD sequence motif within the catalytic loop of the AKT2 kinase domain that is invariant in AKT isoforms in all species and is also highly conserved within the protein kinase family. The RD motif includes the invariant aspartic acid at codon 275 (D275) that performs an essential catalytic function in all protein kinases. Treatment of HepG2 human liver cells with insulin (176730) induced the translocation of endogenous FOXA2 (600288) from the nucleus to the cytosol. While overexpression of wildtype AKT2 mimicked this effect, FOXA2 activity remained entirely nuclear in cells transfected with mutant R274H AKT2. Adipocytes overexpressing mutant AKT2 also showed markedly decreased lipid accumulation. Analysis of the proband's body composition revealed a 35% reduction in total body fat compared to that predicted for height and weight, consistent with the ability of AKT2 R274H to impair adipogenesis and the observation that Akt2 knockout mice develop lipoatrophy as they age (Garofalo et al., 2003).
In 2 patients with insulin resistance due to the R274H mutation, Semple et al. (2009) found features consistent with what they termed 'metabolic dyslipidemia,' including elevated fasting triglycerides, high very low-density lipoprotein (VLDL)/cholesterol ratios, low HDL cholesterol levels, and high LDL levels. They also had increased de novo lipogenesis and hepatic steatosis. The features were similar to those observed in patients with familial lipodystrophy (see, e.g., FPLD2; 151660). In contrast, individuals with mutations in the insulin receptor gene (INSR; 147670) had a relatively normal lipid profile and no hepatic steatosis. Semple et al. (2009) concluded that metabolic dyslipidemia and hepatic steatosis result from selective postreceptor insulin resistance in the liver.
Hypoinsulinemic Hypoglycemia and Hemihypertrophy
In 3 patients with hypoinsulinemic hypoglycemia and hemihypertrophy (HIHGHH; 240900), Hussain et al. (2011) identified heterozygosity for a missense mutation in the AKT2 gene (E17K; 164731.0002). In 2 of the patients, Sanger sequencing was consistent with a de novo germline mutation, whereas the third patient showed 20% mosaicism in lymphocyte and cheek epithelial DNA; no canonical insulin-responsive tissues were available to assess their mutation burden.
Glucose homeostasis depends on insulin responsiveness in target tissues, most importantly, muscle and liver. The critical initial steps in insulin action include phosphorylation of scaffolding proteins and activation of phosphatidylinositol 3-kinase. These early events lead to activation of the serine-threonine protein kinase Akt, also known as protein kinase B. Cho et al. (2001) showed that mice deficient in Akt2 are impaired in the ability of insulin to lower blood glucose because of defects in the action of the hormone on liver and skeletal muscle. Ablation of Akt2 in mice resulted in a mild but statistically significant fasting hyperglycemia due to peripheral insulin resistance and nonsuppressible hepatic glucose production accompanied by inadequate compensatory hyperinsulinemia. Cho et al. (2001) concluded that their data establish Akt2 as an essential gene in the maintenance of normal glucose homeostasis.
Peng et al. (2003) developed Akt1/Akt2 double-knockout (DKO) mice. DKO mice showed severe growth deficiency and died shortly after birth. These mice displayed impaired skin development due to a proliferation defect, skeletal muscle atrophy due to marked decrease in individual muscle cell size, and impaired bone development. The defects were similar to the phenotype of Igf1 receptor (IGF1R; 147370)-deficient mice, suggesting that Akt may serve as an important downstream effector of Igf1r during mouse development. DKO mice also displayed impeded adipogenesis through decreased induction of Pparg (601487).
Woulfe et al. (2004) showed that Akt2 is expressed in mouse platelets and is activated by platelet agonists in a PI3 kinase (see 171833)-dependent pathway. Deletion of the Akt2 gene in mice impaired platelet aggregation, fibrinogen binding, and granule secretion, especially in response to low concentrations of agonists that activate the G protein-coupled receptors for thrombin (176930) and thromboxane A2. Loss of Akt2 also impaired arterial thrombus formation and stability in vivo, despite having little effect on platelet responses to collagen and ADP.
To investigate whether the functions of individual Akt/PKB isoforms are distinct, Garofalo et al. (2003) generated mice lacking Akt2/PKB-beta. Mice lacking this isoform exhibited mild growth deficiency and an age-dependent loss of adipose tissue or lipoatrophy, with all observed adipose depots dramatically reduced by 22 weeks of age. Akt2/PKB-beta-deficient mice were insulin-resistant with elevated plasma triglycerides and showed fed and fasting hyperglycemia, hyperinsulinemia, glucose intolerance, and impaired muscle glucose uptake. In males, insulin resistance progressed to a severe form of diabetes accompanied by pancreatic beta cell failure; in contrast, female Akt2/PKB-beta-deficient mice remained mildly hyperglycemic and hyperinsulinemic until at least 1 year of age. Thus, Akt2/PKB-beta-deficient mice exhibit growth deficiency similar to that reported for mice lacking Akt1/PKB-alpha, indicating that both Akt2/PKB-beta and Akt1/PKB-alpha participate in the regulation of growth. The marked hyperglycemia and loss of pancreatic beta cells and adipose tissue in Akt2/PKB-beta-deficient mice suggested that Akt2/PKB-beta plays critical roles in glucose metabolism and the development or maintenance of proper adipose tissue and islet mass for which other Akt/PKB isoforms are unable to compensate fully.
In a family segregating autosomal dominant type 2 diabetes mellitus (T2D; 125853), George et al. (2004) identified a G-to-A transition in the AKT2 gene, resulting in an arg-to-his substitution at codon 274 (R274H). Family members carrying this mutation were markedly hyperinsulinemic, and the proband, her mother, and maternal grandmother all developed diabetes mellitus in their thirties. Three other first-degree relatives available for study were all clinically normal, with normal fasting glucose and insulin, and were homozygous for the wildtype AKT2 sequence. George et al. (2004) did not identify this mutation in genomic DNA of 1,500 control subjects from the United Kingdom. In 1 of the patients reported by George et al. (2004), Semple et al. (2009) found features consistent with what they termed 'metabolic dyslipidemia,' including elevated fasting triglycerides, high VLDL/cholesterol ratios, low HDL cholesterol levels, and high LDL levels. The patient also had increased de novo lipogenesis and hepatic steatosis.
In 3 patients with hypoinsulinemic hypoglycemia and hemihypertrophy (HIHGHH; 240900), Hussain et al. (2011) identified heterozygosity for a 49G-A transition in the AKT2 gene, resulting in a glu17-to-lys (E17K) substitution in the pleckstrin homology domain. In 2 of the patients, Sanger sequencing was consistent with a de novo germline mutation, whereas the third patient showed 20% mosaicism in lymphocyte and cheek epithelial DNA; no canonical insulin-responsive tissues were available to assess their mutation burden. The mutation was not present in any of the unaffected parents or in 1,130 control genomes and exomes. Mutant AKT2 exhibited plasma membrane localization in serum-starved HeLa cells, and produced inappropriate tonic nuclear exclusion of FOXO1 (FOXO1A; 136533) in 3T3-L1 preadipocytes.
Altomare, D. A., Kozak, C. A., Sonoda, G., Testa, J. R. Chromosome mapping of the mouse Akt2 gene and Akt2 pseudogene. Cytogenet. Cell Genet. 74: 248-251, 1996. [PubMed: 8976376] [Full Text: https://doi.org/10.1159/000134426]
Cheng, J. Q., Godwin, A. K., Bellacosa, A., Taguchi, T., Franke, T. F., Hamilton, T. C., Tsichlis, P. N., Testa, J. R. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc. Nat. Acad. Sci. 89: 9267-9271, 1992. [PubMed: 1409633] [Full Text: https://doi.org/10.1073/pnas.89.19.9267]
Cheng, J. Q., Ruggeri, B., Klein, W. M., Sonoda, G., Altomare, D. A., Watson, D. K., Testa, J. R. Amplification of AKT2 in human pancreatic cancer cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Nat. Acad. Sci. 93: 3636-3641, 1996. [PubMed: 8622988] [Full Text: https://doi.org/10.1073/pnas.93.8.3636]
Cho, H., Mu, J., Kim, J. K., Thorvaldsen, J. L., Chu, Q., Crenshaw, E. B., III, Kaestner, K. H., Bartolomei, M. S., Shulman, G. I., Birnbaum, M. J. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB-beta). Science 292: 1728-1731, 2001. [PubMed: 11387480] [Full Text: https://doi.org/10.1126/science.292.5522.1728]
Garofalo, R. S., Orena, S. J., Rafidi, K., Torchia, A. J., Stock, J. L., Hildebrandt, A. L., Coskran, T., Black, S. C., Brees, D. J., Wicks, J. R., McNeish, J. D., Coleman, K. G. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB-beta. J. Clin. Invest. 112: 197-208, 2003. [PubMed: 12843127] [Full Text: https://doi.org/10.1172/JCI16885]
George, S., Rochford, J. J., Wolfrum, C., Gray, S. L., Schinner, S., Wilson, J. C., Soos, M. A., Murgatroyd, P. R., Williams, R. M., Acerini, C. L., Dunger, D. B., Barford, D., Umpleby, A. M., Wareham, N. J., Davies, H. A., Schafer, A. J., Stoffel, M., O'Rahilly, S., Barroso, I. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304: 1325-1328, 2004. [PubMed: 15166380] [Full Text: https://doi.org/10.1126/science.1096706]
Hussain, K., Challis, B., Rocha, N., Payne, F., Minic, M., Thompson, A., Daly, A., Scott, C., Harris, J., Smillie, B. J. L., Savage, D. B., Ramaswami, U., De Lonlay, P., O'Rahilly, S., Barroso, I., Semple, R. K. An activating mutation of AKT2 and human hypoglycemia. Science 334: 474 only, 2011. [PubMed: 21979934] [Full Text: https://doi.org/10.1126/science.1210878]
Li, X., Monks, B., Ge, Q., Birnbaum, M. J. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1-alpha transcription coactivator. Nature 447: 1012-1016, 2007. [PubMed: 17554339] [Full Text: https://doi.org/10.1038/nature05861]
Peng, X., Xu, P.-Z., Chen, M.-L., Hahn-Windgassen, A., Skeen, J., Jacobs, J., Sundararajan, D., Chen, W. S., Crawford, S. E., Coleman, K. G., Hay, N. Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev. 17: 1352-1365, 2003. [PubMed: 12782654] [Full Text: https://doi.org/10.1101/gad.1089403]
Semple, R. K., Sleigh, A., Murgatroyd, P. R., Adams, C. A., Bluck, L., Jackson, S., Vottero, A., Kanabar, D., Charlton-Menys, V., Durrington, P., Soos, M. A., Carpenter, T. A., Lomas, D. J., Cochran, E. K., Gorden, P., O'Rahilly, S., Savage, D. B. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J. Clin. Invest. 119: 315-322, 2009. [PubMed: 19164855] [Full Text: https://doi.org/10.1172/JCI37432]
Staal, S. P. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc. Nat. Acad. Sci. 84: 5034-5037, 1987. [PubMed: 3037531] [Full Text: https://doi.org/10.1073/pnas.84.14.5034]
Woulfe, D., Jiang, H., Morgans, A., Monks, R., Birnbaum, M., Brass, L. F. Defects in secretion, aggregation, and thrombus formation in platelets from mice lacking Akt2. J. Clin. Invest. 113: 441-450, 2004. [PubMed: 14755341] [Full Text: https://doi.org/10.1172/JCI20267]