Barry Posner

Biography

Polypeptide Hormone Laboratory   

Research Interest

My laboratory focuses on the study of insulin and growth factor action with a particular emphasis on their relationship to the pathogenesis of Type 2 Diabetes Mellitus. Both insulin and IGF bind to their cell surface receptors, which are tyrosine kinases, leading to their activation and internalization into the endosomal system. Novel substrates of both the insulin receptor kinase (IRK) and the EGF receptor kinase (EGFRK) have been identified within endosomes. We identified a novel class of phosphotyrosine phosphatase (PTP) inhibitors - the peroxovanadium (pV) compounds - as potent insulin mimickers. pVs promote activation of the IRK, both in situ and in vivo by inhibiting an IRK-associated PTP, leading to IRK activation and a range of insulin effects, including hypoglycemia in normal and diabetic rats. A current focus is on the role of intraendosomal processes as regulators of IRK function. These include the modulation of intraendosomal pH, a specific endosomal acidic insulinase (EAI), and PTPs, all of which modulate IRK activation and insulin signaling. Defects in one or more of these processes could contribute to the pathogenesis of T2DM. In a recent collaboration we employed Genome wide scanning and proteomics to identify a number of novel genes and proteins which could contribute to the development of T2DM. We are following up these studies to further our understanding of insulin and growth factor signalling and their abnormalities. In this regard emphasis is being placed on how EGF and insulin signalling use very similar intracellular pathways and yet produce responses highly specific to each agent.