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.

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 negative regulator of PI3-kinase in normal cells. In addition constitutively active forms of PI3-kinase are also oncogenic in some species (see table 1).

The proto-oncogene PKB/Akt is a member of the second-messenger regulated subfamily of protein kinases. Receptor-activated PI3-kinase produces PI-3,4,5-P3, leading to membrane attachment and subsequent phosphorylation and activation of PKB/Akt. Activated PKB/Akt is implicated in glucose metabolism, transcriptional control, and in the regulation of apoptosis in many different cell types. Furthermore, it is a central player in a signaling pathway of which many components (including PTEN, a negative regulator of this pathway) have been linked to tumorigenesis. PKB/Akt has been isolated as an oncogene from a mouse lymphoma, where the attachment of the viral gag sequence alters its sub-cellular location leading to constitutive activation of the kinase. Constitutive activation, or the overexpression of PKB/Akt seen in many human tumors, probably contributes to the development of a tumor by blocking apoptosis. Our knowledge of the receptor tyrosine kinase activated PI3-kinase, and downstream effectors, has dramatically increased over the past decade. Deregulation of these signaling pathways is implicated in many different forms of cancer. Although we have identified many of the players in these lipid signaling pathways we still do not have an effective therapeutics that can be utilized to treat various cancers
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Table 1: PI 3-kinase/PTEN/PKB deregulation in human cancer