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Gene Review

AKT2  -  v-akt murine thymoma viral oncogene homolog 2

Homo sapiens

Synonyms: HIHGHH, PKB beta, PKBB, PKBBETA, PRKBB, ...
 
 
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Disease relevance of AKT2

 

High impact information on AKT2

 

Chemical compound and disease context of AKT2

  • The rats bearing well-established C6 gliomas were treated with LXSN-AS-AKT2 DNA or LXSN (empty vector)-lipofectamine complexes intratumorally (treated group and control treated group) [8].
  • Akt2, a homolog of Akt1, encodes a serine/threonine protein kinase that is amplified in ovarian and pancreatic cancers [9].
  • In this report we now show that overexpression of EGFR or activated AKT-2 in MCF-7 cells leads to phosphorylation of Ser167 in the AF-1 domain of ERalpha, enhanced ER-amplified in breast cancer 1 (ER:AIB1) interaction in the presence of tamoxifen, and resistance to tamoxifen [10].
  • 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 [11].
 

Biological context of AKT2

  • Two human homologues of the v-akt oncogene, AKT1 and AKT2, were cloned [2].
  • 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) [12].
  • AKT2 transfectants demonstrated increased adhesion and invasion through collagen IV because of up-regulation of beta1 integrins [3].
  • Targeted reduction of AKT1 expression, but not AKT2, by RNA interference resulted in an abnormal epidermis in organotypic skin cultures with a thin parabasal region and a pronounced but disorganized cornified layer [13].
  • Ectopic expression of constitutively active AKT2 and/or survivin significantly rescue human cancer cells from GGTI-298-induced apoptosis [14].
 

Anatomical context of AKT2

  • In this study, we show that AKT2 in epithelial cells is activated by UV-C irradiation, heat shock, and hyperosmolarity as well as by tumor necrosis factor alpha (TNFalpha) through a phosphatidylinositol 3-kinase-dependent pathway [15].
  • AKT activity increased during keratinocyte differentiation and was attributed to the specific activation of AKT1 and AKT2 [13].
  • Phosphorylated AKT2 in tumor specimens localized to the cell membrane and cytoplasm but not the nucleus [16].
  • APPL is highly expressed in skeletal muscle, heart, ovary and pancreas, tissues in which AKT2 mRNA is abundant [4].
  • 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 [17].
 

Associations of AKT2 with chemical compounds

  • Increased invasion by AKT2 was blocked by preincubation with an anti-beta1 integrin function blocking antibody, exposure to wortmannin, and by expression of phosphatase and tensin homologue tumor suppressor (PTEN) [3].
  • Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2 [4].
  • Genistein may also act by disabling cancer cell self-protection by inhibiting expression of AKT2, CYP1B1, and DNA ligase III [18].
  • Sequence analysis and in vitro translation demonstrated that AKT2 encodes a 56-kDa protein with homology to serine/threonine kinases; moreover, this protein contains a Src homology 2-like domain [19].
  • Importantly, expression of constitutively active AKT1 or AKT2 does not rescue cells from the imatinib-mediated apoptosis although glucose uptake was not blocked, suggesting that the potential therapeutic effect of imatinib is independent of AKT activity and glucose deprivation [20].
 

Enzymatic interactions of AKT2

 

Regulatory relationships of AKT2

 

Other interactions of AKT2

 

Analytical, diagnostic and therapeutic context of AKT2

References

  1. PIK3CA is implicated as an oncogene in ovarian cancer. Shayesteh, L., Lu, Y., Kuo, W.L., Baldocchi, R., Godfrey, T., Collins, C., Pinkel, D., Powell, B., Mills, G.B., Gray, J.W. Nat. Genet. (1999) [Pubmed]
  2. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Staal, S.P. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  3. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Arboleda, M.J., Lyons, J.F., Kabbinavar, F.F., Bray, M.R., Snow, B.E., Ayala, R., Danino, M., Karlan, B.Y., Slamon, D.J. Cancer Res. (2003) [Pubmed]
  4. Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2. Mitsuuchi, Y., Johnson, S.W., Sonoda, G., Tanno, S., Golemis, E.A., Testa, J.R. Oncogene (1999) [Pubmed]
  5. Analysis of genetic variation in Akt2/PKB-beta in severe insulin resistance, lipodystrophy, type 2 diabetes, and related metabolic phenotypes. Tan, K., Kimber, W.A., Luan, J., Soos, M.A., Semple, R.K., Wareham, N.J., O'Rahilly, S., Barroso, I. Diabetes (2007) [Pubmed]
  6. The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Ogg, S., Ruvkun, G. Mol. Cell (1998) [Pubmed]
  7. Akt2, phosphatidylinositol 3-kinase, and PTEN are in lipid rafts of intestinal cells: role in absorption and differentiation. Li, X., Leu, S., Cheong, A., Zhang, H., Baibakov, B., Shih, C., Birnbaum, M.J., Donowitz, M. Gastroenterology (2004) [Pubmed]
  8. The effects of antisense AKT2 RNA on the inhibition of malignant glioma cell growth in vitro and in vivo. Pu, P., Kang, C., Li, J., Jiang, H., Cheng, J. J. Neurooncol. (2006) [Pubmed]
  9. Activation of Akt2 Inhibits anoikis and apoptosis induced by myogenic differentiation. Fujio, Y., Mitsuuchi, Y., Testa, J.R., Walsh, K. Cell Death Differ. (2001) [Pubmed]
  10. Activation function-1 domain of estrogen receptor regulates the agonistic and antagonistic actions of tamoxifen. Glaros, S., Atanaskova, N., Zhao, C., Skafar, D.F., Reddy, K.B. Mol. Endocrinol. (2006) [Pubmed]
  11. AKT involvement in cisplatin chemoresistance of human uterine cancer cells. Gagnon, V., Mathieu, I., Sexton, E., Leblanc, K., Asselin, E. Gynecol. Oncol. (2004) [Pubmed]
  12. AKT2, a member of the protein kinase B family, is activated by growth factors, v-Ha-ras, and v-src through phosphatidylinositol 3-kinase in human ovarian epithelial cancer cells. Liu, A.X., Testa, J.R., Hamilton, T.C., Jove, R., Nicosia, S.V., Cheng, J.Q. Cancer Res. (1998) [Pubmed]
  13. AKT1 Provides an Essential Survival Signal Required for Differentiation and Stratification of Primary Human Keratinocytes. Thrash, B.R., Menges, C.W., Pierce, R.H., McCance, D.J. J. Biol. Chem. (2006) [Pubmed]
  14. Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis. Dan, H.C., Jiang, K., Coppola, D., Hamilton, A., Nicosia, S.V., Sebti, S.M., Cheng, J.Q. Oncogene (2004) [Pubmed]
  15. Inhibition of JNK by cellular stress- and tumor necrosis factor alpha-induced AKT2 through activation of the NF kappa B pathway in human epithelial Cells. Yuan, Z.Q., Feldman, R.I., Sun, M., Olashaw, N.E., Coppola, D., Sussman, G.E., Shelley, S.A., Nicosia, S.V., Cheng, J.Q. J. Biol. Chem. (2002) [Pubmed]
  16. Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer. Yuan, Z.Q., Sun, M., Feldman, R.I., Wang, G., Ma, X., Jiang, C., Coppola, D., Nicosia, S.V., Cheng, J.Q. Oncogene (2000) [Pubmed]
  17. Blockade of AKT activation in prostate cancer cells with a small molecule inhibitor, 9-chloro-2-methylellipticinium acetate (CMEP). Zhang, M., Fang, X., Liu, H., Wang, S., Yang, D. Biochem. Pharmacol. (2007) [Pubmed]
  18. Genistein-induced changes in gene expression in Panc 1 cells at physiological concentrations of genistein. Bai, J., Sata, N., Nagai, H., Wada, T., Yoshida, K., Mano, H., Sata, F., Kishi, R. Pancreas (2004) [Pubmed]
  19. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Cheng, J.Q., Godwin, A.K., Bellacosa, A., Taguchi, T., Franke, T.F., Hamilton, T.C., Tsichlis, P.N., Testa, J.R. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  20. Therapeutic effect of imatinib in gastrointestinal stromal tumors: AKT signaling dependent and independent mechanisms. Tarn, C., Skorobogatko, Y.V., Taguchi, T., Eisenberg, B., von Mehren, M., Godwin, A.K. Cancer Res. (2006) [Pubmed]
  21. AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: implication of AKT2 in chemoresistance. Yuan, Z.Q., Feldman, R.I., Sussman, G.E., Coppola, D., Nicosia, S.V., Cheng, J.Q. J. Biol. Chem. (2003) [Pubmed]
  22. MAPKAPK-2 is a critical signaling intermediate in NHE3 activation following Na+-glucose cotransport. Hu, Z., Wang, Y., Graham, W.V., Su, L., Musch, M.W., Turner, J.R. J. Biol. Chem. (2006) [Pubmed]
  23. Frequent activation of AKT2 kinase in human pancreatic carcinomas. Altomare, D.A., Tanno, S., De Rienzo, A., Klein-Szanto, A.J., Tanno, S., Skele, K.L., Hoffman, J.P., Testa, J.R. J. Cell. Biochem. (2003) [Pubmed]
  24. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. Irie, H.Y., Pearline, R.V., Grueneberg, D., Hsia, M., Ravichandran, P., Kothari, N., Natesan, S., Brugge, J.S. J. Cell Biol. (2005) [Pubmed]
  25. Only Akt1 Is Required for Proliferation, while Akt2 Promotes Cell Cycle Exit through p21 Binding. H??ron-Milhavet, L., Franckhauser, C., Rana, V., Berthenet, C., Fisher, D., Hemmings, B.A., Fernandez, A., Lamb, N.J. Mol. Cell. Biol. (2006) [Pubmed]
  26. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Levine, D.A., Bogomolniy, F., Yee, C.J., Lash, A., Barakat, R.R., Borgen, P.I., Boyd, J. Clin. Cancer Res. (2005) [Pubmed]
  27. Mutational Analysis of AKT1, AKT2 and AKT3 Genes in Common Human Carcinomas. Soung, Y.H., Lee, J.W., Nam, S.W., Lee, J.Y., Yoo, N.J., Lee, S.H. Oncology (2006) [Pubmed]
  28. alpha-TEA inhibits survival and enhances death pathways in cisplatin sensitive and resistant human ovarian cancer cells. Yu, W., Shun, M.C., Anderson, K., Chen, H., Sanders, B.G., Kline, K. Apoptosis (2006) [Pubmed]
  29. Akt/protein kinase B isoforms are differentially regulated by epidermal growth factor stimulation. Okano, J., Gaslightwala, I., Birnbaum, M.J., Rustgi, A.K., Nakagawa, H. J. Biol. Chem. (2000) [Pubmed]
  30. Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cheng, G.Z., Chan, J., Wang, Q., Zhang, W., Sun, C.D., Wang, L.H. Cancer Res. (2007) [Pubmed]
  31. Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Pedrero, J.M., Carracedo, D.G., Pinto, C.M., Zapatero, A.H., Rodrigo, J.P., Nieto, C.S., Gonzalez, M.V. Int. J. Cancer (2005) [Pubmed]
  32. Akt2 regulates cardiac metabolism and cardiomyocyte survival. Debosch, B., Sambandam, N., Weinheimer, C., Courtois, M., Muslin, A.J. J. Biol. Chem. (2006) [Pubmed]
 
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