This is a revised application originally designed to test the idea that specific protein tyrosine phosphatases (PTPases) have a role in regulation of the reversible tyrosine phosphorylation of the insulin receptor (IR) and its substrates. The PI's laboratory has provided compelling evidence for the involvement of PTPases in negative regulation of insulin action. Specifically, leucocyte common antigen related """"""""LAR"""""""" PTPase, a transmembrane receptor-type enzyme and PTP1B, a non-receptor-type phosphatase have been shown, by loading cells with neutralizing antibodies and by use of anti-sense methods, to dephosphorylate the insulin receptor and thus affect insulin action. Several submitted manuscripts document that LAR overexpression downregulates the effect of insulin as predicted if LAR inactivates the insulin receptor by dephosphorylation. An additional manuscript documents the physical interaction of LAR with the insulin receptor using anti-LAR antibodies to immunoprecipitate the LAR-IR complex. Paradoxically, LAR knockout mice appear phenotypically normal indicating there must be a redundant pathway. The present application proposes to: 1) Further characterize how LAR and PTP1B modulate the insulin receptor kinase in intact cells by osmotic loading of inhibitory antibodies and by cell transfections with constructs expressing dominant negative LAR. The proposed studies include looking at the phosphorylation state of IRS-1, Shc and the insulin receptor, and determining if LAR is co-localized in the endoplasmic reticulum with the insulin receptor. 2) Determine the molecular mechanism by which LAR and PTP1B regulate the kinase activity of the insulin receptor. Studies on the physical interaction of LAR and PTP1B with the insulin receptor are proposed along with determination of which tyrosines in the insulin receptor are dephosphorylated by these PTPases. 3) Evaluate whether certain PTPases have a catalytic specificity towards functional phosphotyrosines on IRS-1 and Shc as measured by PTPase induced changes in complex formation with adaptor proteins in vitro.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG2-GMA-2 (01))
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Margolis, Ronald N
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Thomas Jefferson University
Internal Medicine/Medicine
Schools of Medicine
United States
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