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Barry I. Posner, O.C., M.D., FRS(C) Professor of Medicine Associate Member: Departments of Physiology and Chemistry Full Member: Anatomy and Cell Biology Director, Polypeptide Hormone Laboratory, McGill University |
Research:
Receptor Tyrosine Kinases; Insulin; Insulin-like growth factors (IGFs).
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.
Selected Publications:
Lavoie, C.E., E. Chevet, L. Roy, N.K. Tonks, A. Fazel, B.I. Posner, J. Paiement and J.J.M. Bergeron. Tyrosine phosphorylation of p97 regulates transitional endoplasmic reticulum assembly. PNAS 97: 13637-13642, 2000.
Doillon, C.J., R.L. Faure, B.I. Posner and P.E. Savard. Peroxovandium compounds as inhibitors of angiogenesis. Angiogenesis 3: 361-369, 2000.
Mounier, C., L. Lavoie, V. Dumas, K. Mohammad-Ali, J. Wu, A. Nantel, J.J.M. Bergeron D.Y./ Thomas and B.I. Posner. Specific inhibition by hGRB10ζ of insulin-induced glycogen synthase activation: evidence for a novel signaling pathway. Mol./ Cell. Endo. 173: 15-27, 2001.
Balbis, A., Baquiran, G., Dumas, V., and B. I. Posner. Effect of inhibiting vacuolar acidification on insulin signaling in hepatocytes. J. Biol. Chem. 279: 12777-12785, 2004.
Balbis, A., G.Baquiran, and B.I.Posner. Effect of Insulin on Caveolin-enriched Membrane Domains in Rat Liver. J.Biol. Chem. 279: 39348 – 39357, 2004.
Li, C.H., G. Baquiran, M.Tremblay, A. Fazel, J. J.M. Bergeron, and B.I.Posner. IRK-associated PTPs in Hepatocyte Endosomes: Assessing the Role of PTP1B. Endocrinology 147: 912-18, 2006.
Mounier, C., Dumas, V., and B.I. Posner. Regulation of Hepatic Insulin-like Growth Factor-Binding Protein-1 (IGFBP-1) Gene Expression by Insulin: Central Role for mTOR Independent of Foxo Proteins. Endocrinology 147: 2383- 2391, 2006.
Mounier, C. and B.I.Posner. Transcriptional regulation by insulin: from the receptor to the gene. Can J Physiol Pharmacol. 84(7):713-724, 2006.
Balbis, A., A. Parmar, Y.Wang, G.Baquiran, and B.I.Posner. Compartmentalization of Signaling Competent EGFR in Endosomes. Endocrinology 148: 2944-2954, 2007.
Sladek, R. G.Rocheleau, J.Rung, C.Dina et al. A Genome Wide Association Study Identifies Novel Susceptibility Loci for Type 2 Diabetes Mellitus. Nature 445:881-885, 2007.