AKT signaling in physiology and disease.

The serine/threonine kinase AKT functions as a critical mediator of signaling downstream of PI3 kinase. Studies over the last two decades have firmly established the importance of AKT in the regulation of cell survival, proliferation, and insulin-dependent metabolic cell responses. AKT executes these diverse tasks through phosphorylation of numerous cellular substrates. Substantial progress has been made in understanding the regulation of AKT activity by upstream kinases and elucidating downstream mechanisms that mediate its myriad cellular effects. Here, we present an overview of AKT regulation and function in physiological and pathological settings. An emphasis is placed on the involvement of aberrant AKT signaling in human diseases ranging from diabetes to cancer and neurological diseases.

AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.

Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations.