STRUCTURE AND FUNCTION OF THE BETA CYTOPLASMIC DOMAINS

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The cytoplasmic domains of integrins provide an important link between the ligand binding sequences in the extracellular domain and cytoplasmic components responsible for transducing signals to intracellular pathways. For activatable integrins such as alphaIIb/beta3, the cytoplasmic domains also provide a link for inside-out signals from cytoplasmic pathways to the extracellular ligand binding sequences. Despite this increased recognition of integrins as signal mediating receptors, the precise nature of these signals, the identification of those that are generated directly be integrins and those that are secondarily generated by integrins, and the relationship between these signals remain uncertain. The overall aim of this project is to identify cytoplasmic domain sequences which interact with and mediate integrin-associated signals and to use this structural information to gain a better understanding of the nature of the signals. Using site-directed mutagenesis and peptide approaches, minimal sequences in the beta 3 cytoplasmic domain which interact with alpha-actinin, talin, vinculin, and other components of integrin-associated focal adhesions will be mapped. Cytoplasmic domain sequences which interact with focal adhesion kinase (pp125/FAK) and paxillin and the role that these interactions have in focal adhesion formation and integrin activation will also be determined. The potential role of phosphorylation of tyrosine residues in the cytoplasmic tail of beta 3 and the role that phosphorylation plays in signal mediation will be examined. Finally, sequences required for the interaction and responses of integrins to components of the MAP kinase cascade and the regulation of integrin activation by H-ras and R-ras will be identified.