Abstract
AKT/PKB (protein kinase B) kinases mediate signaling pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase. AKT kinases regulate diverse cellular processes including cell proliferation and survival, cell size and response to nutrient availability, tissue invasion and angiogenesis. Many oncoproteins and tumor suppressors implicated in cell signaling/metabolic regulation converge within the AKT signal transduction pathway in an equilibrium that is altered in many human cancers by activating and inactivating mechanisms, respectively, targeting these inter-related proteins. We review a burgeoning literature implicating aberrant AKT signaling in many sporadic human cancers as well as in several dominantly inherited cancer syndromes known as phakomatoses. The latter include disorders caused by germline mutations of certain tumor suppressor genes, that is, PTEN, TSC2/TSC1, LKB1, NF1, and VHL, encoding proteins that intersect with the AKT pathway. We also review various pathogenic mechanisms contributing to activation of the AKT pathway in human malignancy as well as current pharmacologic strategies to target therapeutically components of this pathway.
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Acknowledgements
This work was supported by NIH Grants CA77429, CA83638 (SPORE in Ovarian Cancer), and CA06927, and by an appropriation from the Commonwealth of Pennsylvania to the Fox Chase Cancer Center.
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Altomare, D., Testa, J. Perturbations of the AKT signaling pathway in human cancer. Oncogene 24, 7455–7464 (2005). https://doi.org/10.1038/sj.onc.1209085
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