The IR and integrin receptor signal transduction pathways share several key components and crosstalk between these receptor pathways has recently become apparent. However, the mechanism of this crosstalk and its relevance to insulin action have not been explored. Using primary hepatocytes, we have now observed positive modulation of insulin receptor signal transduction and enhancement of glycogen synthesis in response to integrin engagement. The first objective of this research proposal is to expand these preliminary results and provide experimental support for hypothesis number 1: crosstalk between the IR and integrin receptors modulates hepatic IR signaling and glucose metabolism. The PTP LAR, a transmembrane protein localized to the focal adhesions, appears to be an important component of IR-integrin crosstalk. Using SV40 immortalized liver cells from LAR-/- mice, we observe a defect in cell spreading on fibronectin and alteration in integrin-dependent tyrosine phosphorylation. LAR also appears to affect growth factor receptor signaling by a mechanism requiring the integrin pathway. A second objective of this proposal is to provide experimental support for hypothesis number 2: PTP LAR plays a role in IR-integrin crosstalk through its interaction with the integrin signaling pathway. With the long term goal of defining regulation of insulin receptor signal transduction in insulin target cells, the following specific aims will be pursued:
Specific Aim number 1: Elucidate the mechanism of crosstalk between the integrin receptor and the IR using primary hepatocytes (and cell lines when necessary) and characterize effects on glucose metabolism.
Specific Aim number 2: Define the role of PTP LAR in integrin receptor signaling. The effect of LAR on integrin-dependent tyrosine phosphorylation, activation of the small GTPases rho, rac, and cdc42, and cytoskeleton rearrangement will be investigated.
Specific Aim number 3: Define the role of PTP LAR in crosstalk between the integrin receptor and the IR. Both immediate post-receptor signaling and insulin-dependent effects on glucose metabolic will be examined. The objectives outlined above will characterize the integrin receptor signaling pathway and its influence on IR signaling. Results of this work will shed light on this poorly understood yet potentially important interaction. A greater understanding of the importance of cellular influences on insulin action is the goal.
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