Akt Signaling

The serine/threonine protein kinase Akt/PKB is the cellular homologue of the viral oncogene v-Akt and is activated by various growth and survival factors. In mammals, there are three known isoforms of the Akt kinase, Akt1, Akt2, and Akt3. Many cell surface receptors induce the production of second messengers that activate phosphoinositide 3-kinase (PI3K). Akt is located downstream of PI3K and, therefore, functions as part of a wortmannin-sensitive signaling, pathway. PI3K generates phosphorylated phosphatidylinositides (PI-3,4-P₂ and PI-3,4,5-P₃) in the cell membrane that bind to the amino-terminal pleckstrin homology (PH) domain of Akt. PI-3,4-P₂ and PI-3,4,5-P₃ also activate phosphoinositide-dependent kinase (PDK) which phosphorylates Thr³⁰⁸ of membrane-bound Akt. Ser⁴⁷³ is phosphorylated by integrin-linked kinase (ILK). Activated Akt promotes cell survival through two distinct pathways: 1) Akt inhibits apoptosis by phosphorylating the Bad component of the Bad/Bcl-X_L complex. Phosphorylated Bad binds to 14-3-3 causing dissociation of the Bad/Bcl-X_L complex and allowing cell survival. 2) Akt activates IKK-a that ultimately leads to NF-kb activation and cell survival.

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References:

Yoganathan, T.N., et al., Integrin-linked kinase (ILK) : a "hot" therapeutic target. Biochem. Pharmacol., 60 1115-1119 (2000).

Galetic, I., et al., Mechanism of protein kinase B activation by insulin/insulin-like growth factor-1 revealed by specific inhibitors of phosphoinositide 3-kinase-significance for diabetes and cancer. Pharmacol. Ther., 82, 409-425 (1999).

Kandel, E.S., and Hay, N., The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp. Cell Res., 253, 210-229 (1999).