Akt/PKB Signaling

• Description
• Reviews
• Pathway Key
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Pathway Description:

Since its discovery as a protooncogene over ten years ago, the serine/threonine kinase Akt, also known as protein kinase B (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 three Akt isoforms (Akt1, Akt2 and Akt3) mediate many of the downstream events regulated by PI3K. For instance, Akt is a major regulator of insulin signaling and glucose metabolism, with genetic studies in mice revealing a central role for Akt2 in these processes. Akt regulates cell growth through its effects on the mTOR and p70 S6 kinase 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 Bad and the Forkhead family of transcription factors. Akt has been shown to regulate proteins involved in neuronal function including GABA receptor, Ataxin-1 and Huntingtin proteins. Recently, Akt has been demonstrated to interact with Smad molecules to regulate TGFβ signaling. These findings make Akt/PKB an important therapeutic target for the treatment of cancer, diabetes, stroke and neurodegenerative disease.

Selected Reviews:

• Brazil DP, Yang ZZ, Hemmings BA (2004) Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem. Sci. 29(5), 233–42.
• Brazil DP, Park J, Hemmings BA (2002) PKB binding proteins. Getting in on the Akt. Cell 111(3), 293–303.
• Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296(5573), 1655–7.
• Shiojima I, Walsh K (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ. Res. 90(12), 1243–50.
• Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2(7), 489–501.
• Woodgett JR (2005) Recent advances in the protein kinase B signaling pathway. Curr. Opin. Cell Biol. 17(2), 150–7.

CST would like to thank Prof. Michael Scheid, York University, Toronto, Ontario, for contributing to this diagram.

created January 2003 • revised December 2007