First identified as a growth factor-inducible immediate-early gene in mouse fibroblasts, cyr61 encodes a cysteine-rich and heparin- binding protein that is secreted and associates with the extracellular matrix. A member of an emerging gene family, cyr61 has relatives from Drosophila to man. Expression of cyr61 during mouse embryogenesis is tissue-specific and temporally regulated, suggesting that it may play a developmental role. In recent studies, the Cyr61 protein has been purified in a biologically active form and shown to possess remarkable functional versatility. Thus, purified Cyr61 protein mediates cell adhesion, stimulates chemotaxis, augments growth factor-induced DNA synthesis, enhances cell survival, promotes chondrogenic differentiation in limb mesenchyme, induces angiogenesis in vivo, and promotes tumor growth and vascularization in mice. Cyr61 is a non-RGD-containing ligand of the integrin receptor alpha-v beta-3 and at least the cell adhesion and chemotactic activities of Cyr61 are mediated through this integrin. In this proposal, experiments are designed to elucidate the mechanistic aspects of Cyr61 actions, and to further define the functional roles of Cyr61 in the context of the whole organism. First, since Cyr61 does not contain the RGD sequence motif that is recognized by many integrins, the specific sequence of Cyr61 that interacts with the integrin alpha-v beta-3 will be defined and Cyr6l mutants that disrupt integrin binding will be analyzed. Second, other integrins or cell surface receptors that might bind Cyr61 will be identified and characterized. Third, the structure and function relationships of Cyr61 will be established through the construction and analysis of deletion mutants. The signaling capabilities of these Cyr61 mutants will be analyzed and correlated to their altered functions. Finally, targeted disruption of cyr61 will be constructed in transgenic mice as a means to evaluate its role in development. Through these studies, a better understanding of how Cyr61 can function in such diverse yet important biological processes may emerge.
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