Research in my laboratory focused on a family of proteins that are key elements in the insulin-signaling pathway. Critical steps in insulin action include the initial phosphorylation of adapter proteins associated with the insulin receptor and subsequent activation of the Class Ia phosphatidylinositol 3-kinase (PI3K). One of the key components in this process is protein kinase B (PKB/Akt), which couples the activation of insulin receptors to intracellular processes controlling glucose uptake, cell growth, cell survival (anti-apoptosis), angiogenesis and gene regulation (see below).

During the past two decades a significant amount of cancer research focused on the Ras oncogene for the simple reason that it was the first identified oncogene, and because of its prevalence in human cancer. Over the past few years another signaling pathway downstream of receptor tyrosine kinases has emerged, namely, the PI 3-kinase/PTEN/PKB pathway. Several components of this pathway are deregulated in many different forms of human cancer. Significantly the PTEN tumor suppressor gene, a phosphoinositide (PIP3) phosphatase is the second most frequently mutated gene after p53 in human cancer.

Many proto-oncogene receptor tyrosine kinases (specific for ligands such as IGF-1, PDGF, EGF, FGF another cytokines) signal through an autophosphorylation driven recruit-ment of phosphoinositide 3-kinase (PI3-kinase). PI3-kinase plays a major role in the regulation of cell growth, cell survival and cell migration through the generation of lipid second messenger¡¯s phosphatidylinositol-3,4-bisphosphate (PI-3,4-P2) and phosphatidyl-inositol-3,4,5-trisphosphate (PI-3,4,5-P3) that regulate a diverse set of signaling pathways.

A variety of proteins decode the lipid second messenger signals by specifically binding to the lipid products of PI3-kinase. These include the cytoplasmic tyrosine kinases of the TEC/BTK family, Ser/Thr protein kinases of the PKB/Akt and PDK-1 families, adaptor proteins of the IRS/GAB family and other PH domain containing proteins, such as the exchange factors of GTP binding proteins. All these proteins bind PI-3,4-P2 and PI-3,4,5-P3 leading to membrane localization following PI3-kinase activation. By recruiting and activating signaling complexes PI3-kinase coordinates a complex series of signaling events. A role for PI3-kinase in human cancer has been inferred from the fact that the tumor suppressor gene, PTEN, a lipid phosphatase that dephosphorylate the 3 position of the inositol ring, acts as a negativ regulaor of P3-kinas in noral cels. In dditionconstittively @ctive frms of I3-kinae are aso oncoenic n some pecies see tabe 1).