Members of the integrin family of cell adhesion receptors play a vita role in the generation and maintenance of cell and tissue architecture. In addition, it is now clear that integrins mediate biologically significant signal transduction processes. Thus, integrins can directly activate certain signaling pathways and can also modulate growth and differentiation pathways downstream of receptor tyrosine kinases. Recent work from the applicant's laboratory and others has now demonstrated that integrin mediated cell anchorage can also regulate signaling from heptahelical G Protein-Coupled Receptors (GPCRs) to the MAP Kinase (MAPK) cascade. In this grant, the applicant proposes to elucidate the mechanistic basis of integrin modulation of GPCR signaling, focusing on Gq and Gi linked receptors. They will identify the locus in the signaling path between GPCRs and MAPK that is regulated by cell anchorage for both the Gq and Gi pathways. They will determine if specific integrins are involved in anchorage regulation of GPCR signaling, and investigate the structural basis of integrin specificity. The role of cytoskeletal or regulator proteins associated with focal adhesion sites in GPCR signaling will be examined. The relationship between integrin modulation of GPCR signaling to MAPK, and regulation of the cell cycle will also be investigated. In particular, is there integrin specificity and/or G-protein specificity in the connection between anchorage regulated GPCR signaling and cell cycle events? These studies have the potential to provide fundamental insights into the mechanism(s) of integrin regulation of G protein coupled signaling cascades, with important implications for understanding of cell proliferation and differentiation.
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