Integrin mediated cell adhesion to the extracellular matrix is essential for the maintenance of tissue architecture and for cell survival, proliferation and differentiation. Adhesion occurs in discrete steps. It is initiated by the binding of integrins to their substrate ligands in cell attachment. Integrin engagement activates signaling pathways that promote cell spreading. Importantly, cell spreading is required for adhesion to promote cell survival and proliferation. Since integrin beta subunit cytoplasmic (beta-tails) domains are required for cell spreading, the principal investigator has focused on understanding the mechanisms by which beta tails regulate cell spreading. The goal of the principal investigator's laboratory is to understand how beta tails, integrin-activated signaling pathways, and specific beta tail binding proteins cooperate to regulate cell spreading. The experimental approach is to express integrin beta tails as isolated domains connected to the transmembrane-linked extracellular domain of the tac subunit of the lL2-receptor (tac-beta tail chimeras). Tac-beta tail chimeras can function as dominant inhibitors of integrin mediated cell spreading, and when clustered on the cell surface tac-beta tail chimeras activate signaling pathways similar to endogenous integrins, presumably by binding to the same cellular proteins as endogenous Beta tails. Recently, the principal investigator demonstrated that the expression of activated mutants of PKC-epsilon, PI3-kinase, R-Ras and Rac-1 each restored cell spreading inhibited by tac-beta-1 and identified Rac1 as an important component of this pathway. Experiments are proposed to identify downstream targets of Rac1 which are important in this process. Since current evidence suggests that Rap1 may also be an important regulator of cell adhesion, the principal investigator proposes to characterize the role of Rap1 in cell spreading. Tac-beta-1 may inhibit cell spreading by disrupting the formation of signaling complexes with endogenous integrins that promote the activation of tyrosine kinases and their downstream targets including Rac1. Experiments are proposed to test this hypothesis. A long-term goal is to identify proteins that bind to the beta-tail to regulate cell spreading. The principal investigator has recently identified ICAP-1, FAK and/or paxillin as potential candidates. Experiments are proposed to functionally characterize these interactions and to determine whether additional interactions with the 13-tail are required to regulate cell spreading.
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