Perturbations of the AKT signaling pathway in human cancer.
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.
Altomare
Deborah A
DA
Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Testa
Joseph R
JR
D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000503:physiopathology; D009389:Neovascularization, Pathologic; D011494:Protein Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases