My research interests lie in the molecular mechanisms of insulin signaling. Insulin is the primary anabolic hormone in the body, and is released from the pancreas after a meal to stimulate glucose uptake into muscle, liver and fat. The relevance of insulin signaling pathways is illustrated by the fact that an absence of insulin production, or deregulation of insulin signaling in tissues such as liver, leads to the disease states termed type I and type II diabetes, respectively.
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.
