PI3K / Akt Signaling

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PI3K / Akt Signaling

Pathway Description:

Since its initial discovery as a proto-oncogene, the serine/threonine kinase Akt (also known as protein kinase B or PKB) has become a major focus of attention because of its critical regulatory role in diverse cellular processes, including cancer progression and insulin metabolism. The Akt cascade is activated by receptor tyrosine kinases, integrins, B and T cell receptors, cytokine receptors, G-protein-coupled receptors and other stimuli that induce the production of phosphatidylinositol 3,4,5 triphosphates (PtdIns(3,4,5)P3) by phosphoinositide 3-kinase (PI3K). These lipids serve as plasma membrane docking sites for proteins that harbor pleckstrin-homology (PH) domains, including Akt and its upstream activator PDK1. The tumor suppressor PTEN is recognized as a major inhibitor of Akt and is frequently lost in human tumors. Recently, there has been increased focus on phosphatases that can inactivate Akt, including PHLLP.

There are three highly related isoforms of Akt (Akt1, Akt2, and Akt3) and these represent the major signaling arm of PI3K. For example, Akt is important for insulin signaling and glucose metabolism, with genetic studies in mice revealing a central role for Akt2 in these processes. In addition, germline mutations of Akt have been identified in pathological conditions of cancer and insulin metabolism.

Akt regulates cell growth through its effects on the TSC1/TSC2 complex and mTOR pathways, as well as cell cycle and cell proliferation through its direct action on the CDK inhibitors p21 and p27, and its indirect effect on the levels of cyclin D1 and p53. Akt is a major mediator of cell survival through direct inhibition of pro-apoptotic signals such as the pro-apoptotic regulator Bad and the Fox0 and Myc family of transcription factors. T lymphocyte trafficking to lymphoid tissues is controlled by the expression of adhesion factors downstream of Akt. In addition, Akt has been shown to regulate proteins involved in neuronal function including GABA receptor, ataxin-1, and huntingtin proteins. Akt has been demonstrated to interact with Smad molecules to regulate TGF-β signaling. Finally, lamin A phosphorylation by Akt could play a role in the structural organization of nuclear proteins. These findings make Akt/PKB an important therapeutic target for the treatment of cancer, diabetes, laminopathies, stroke, and neurodegenerative disease.

Selected Reviews:

• Bhaskar PT, Hay N (2007) The two TORCs and Akt. Dev. Cell 12(4), 487–502.
• Bozulic L, Hemmings BA (2009) PIKKing on PKB: regulation of PKB activity by phosphorylation. Curr. Opin. Cell Biol. 21(2), 256–61.
• Brugge J, Hung MC, Mills GB (2007) A new mutational AKTivation in the PI3K pathway. Cancer Cell 12(2), 104–7.
• Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF (2008) The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets 8(3), 187–98.
• Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8(8), 627–44.
• Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7), 1261–74.
• Salmena L, Carracedo A, Pandolfi PP (2008) Tenets of PTEN tumor suppression. Cell 133(3), 403–14.

We would like to thank Prof. Michael Scheid, York University of Toronto, Ontario, Canada for reviewing this diagram.