Integrins are a major class or transmembrane, alpha/beta, heterodimeric receptor used by cells to interact with the extracellular matrix. Their function is required in a variety of cellular processes, including cell adhesion, cell migration, matrix assembly, cytoskeletal organization, and signal transduction. These processes are important in embryonic development, wound healing, tumor metastasis, tissue organization and immune response. Current evidence suggests that beta intracellular domains are required for most of the cytoplasmic functions of integrins. Therefore, beta intracellular domains are likely to be important links in the cascade of events by which the extracellular matrix affects cell behavior. However, the cytoplasmic interactions that mediate beta intracellular domain function remain largely undefined. The eight integrin beta intracellular domains identified to date share varying degrees of amino acid sequence homology, suggesting that they possess both overlapping and distinct function. Most cells express a variety of integrin receptors, suggesting that an individual cell's response to the extracellular matrix may depend on the specific beta intracellular domains it expresses. Understanding the roles of the individual beta intracellular domains in mediating responses of the cell to its extracellular matrix is therefore essential to understanding tahe biology of this response. In order to study integrin intracellular domain function, various wild-type and mutant beta intracellular domains, fused to the extracellular and transmembrane domain of the small subunit of the human interleukin-2 (IL- 2), receptor, will be expressed in cultured human fibroblasts. These chimeric receptors, in which the IL-2 receptor portion of the chimera serves only as a reporter of intracellular function, will be tested for their ability to mimic or inhibit various aspects of integrin receptor function. This approach has already been successful in demonstrating that specific beta intracellular domains, when expressed in chimeric receptors, can signal tyrosine phosphorylation of specific cytoplasmic proteins, direct receptor localization to adhesion sites, and inhibit integrin function in cell spreading. The specific goals of this proposal are to define subdomains within the beta1 intracellular domain that are required to mediate various integrin functions, to compare the function of other integrin beta intracellular domains to determine which intracellular functions are shared among beta intracellular domains and which functions are distinct, and then to identify the cytoplasmic proteins that interact with specific beta intracellular subdomains to mediate integrin function.
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