The AKT (or PKB) signaling pathway has been the subject of intense investigation for over a decade as it regulates a multitude of cellular processes including cell proliferation and survival, cell size and response to nutrient availability, glucose metabolism, tissue invasion and angiogenesis. AKT functions as a cardinal nodal point in this pathway for transducing extracellular (growth factor and insulin) and intracellular (receptor tyrosine kinases, Ras and Src) signals. The AKT pathway is ubiquitous in nature and operates in cells to regulate fundamental cellular processes.

AKT, a serine/threonine kinase, is a central component in the AKT pathway and exists as three isoforms in mammals (AKT1, AKT2 and AKT3). AKT is downstream of a key lipid kinase target, PI3K, which is responsible for the generation of the PIP3 phospholipid second messenger. Activation of AKT requires binding to PIP3 via the pleckstrin homology domain and activation loop phosphorylation on AKT at Thr308 by PDK1 and phosphorylation within the carboxy-terminus at Ser473 by PDK2 (1).

Alterations in the AKT pathway, and specifically AKT itself, have been detected in a number of human malignancies (2). Ectopic expression of AKT, especially constitutively activated AKT, is sufficient to induce oncogenic transformation of cells and tumor formation in transgenic mice as well as chemoresistance. Many tumors and tumor cells display elevated AKT protein expression and activity, and many of the proteins which regulate AKT itself (i.e., PI3K, PTEN, Ras, Src and tyrosine kinases) are also often mutated in cancer. Blockage of AKT signaling results in apoptosis and growth inhibition of tumor cells with elevated AKT. The observed dependence of certain tumors on AKT signaling for survival and growth has wide implications for cancer therapy, offering the potential for preferential tumor cell killing. In the last several years, through combinatorial chemistry, high-throughput and virtual screening, and traditional medicinal chemistry efforts, a number of inhibitors of the AKT pathway have been identified that are being further pursued for clinical utility (3).

REFERENCES
1. Vanhaesebroeck, B., et al.: The PI3K-PDK1 connection: more than just a road to PKB. Biochem J. 2000 Mar 15;346 Pt 3:561-76.
2. Altomare, D. A., et al.: Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005 Nov 14;24(50):7455-64.
3. Kumar, C. C., et al.: AKT crystal structure and AKT-specific inhibitors. Oncogene. 2005 Nov 14;24(50):7493-501.