Cell adhesion to the extracellular matrix mediated by the integrin family of cell surface receptors is a crucial physiological determinant of cell proliferation and cell survival. A long term goal of this proposal is to define the mechanism of adhesion dependent cell signaling. How the information that originates when integrins bind to the extracellular matrix is processed to initiate intracellular signals is not known. We have recently identified a novel 200 amino acid protein, Icap1alpha, that specifically interacts with beta1 integrins. We have sown that the binding of Icap1alpha to beta1 integrins request the conserved C-terminal Asn-Pro-Lys-Tyr motif and Valine 792 of the beta1 integrin cytoplasmic domain. In addition, we have demonstrated that Icap1alpha undergoes an adhesion dependent protein phosphorylation. In this proposal, we will study the proximal events of integrin signaling, focusing on the interaction between Icap1alpha and the beta1 integrin cytoplasmic domain. First, a structure-function analysis of Icap1alpha will be carried out. The amino acid sequence requirements for the interaction between the beta1 integrin and Icap1alpha, and the subcellular localization of Icap1alpha will be determined. Second, the amino acid sequences on the beta1 integrin cytoplasmic domain that are required for the initiation of intracellular signaling will be characterized. The hypothesis that Icap1alpha is involved in integrin- mediated signaling will be tested by studying the effects of Valine792 mutation on cell adhesion and cell proliferation. Third, the function of Icap1alpha, in the context of integrin-mediated intracellular signaling events, will be investigated. Both the wild type Icap1alpha and Icap1beta, an Icap1alpha variant that does not bind to beta1 integrins, will be expressed in the cell to determine the function of Icap1alpha. Proteins that interact with Icap1alpha will be identified. Results from this study will enhance our understanding of adhesion- dependent cell signaling and may provide a knowledge basis for modulating cell adhesion and cell proliferation.
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