CCN1, or CYR61, is a cysteine-rich, secreted matricellular protein with diverse regulatory functions. Encoded by a growth factor-inducible immediate-early gene, the expression of CCN1 is dynamic and developmentally controlled. The biological significance of CCN1 is underscored by the observation that CCNI-null mice suffer embryonic death due to vascular defects. CCN1 induces angiogenesis in vivo and promotes tumor growth. Furthermore, aberrant expression of CCN1 is associated with pathological conditions including wound healing, atherosclerosis and restenosis, and human cancer. On the cellular level, purified CCN1 supports cell adhesion, stimulates cell migration, enhances mitogenesis, promotes cell survival, and induces chondrogenic differentiation in limb mesenchyme. CCN1 can induce the expression of genes involved in angiogenesis and matrix remodeling, suggesting that the control of these processes might underlie the biological roles of CCN1 in several contexts, including vessel morphogenesis, skeletal development, wound repair, and tumor growth. Mechanistically, CCN1 functions through direct binding to distinct integrin receptors to mediate disparate activities in a cell type- and context-specific manner. The proangiogenic activities of CCN1 are mediated by its binding through non-canonical sites to integrins (v(3 and (6(1,requiting cell surface heparan sulfate proteoglycans in some contexts. In this proposal, experiments are designed to address the structure, function, and mechanism of actions ofCCN1. First, the binding sites of CCN1 for integrins alphavbeta3, alpha6beta1, and heparan sulfate proteoglycans will dissected through mutagenesis. Second, the signaling pathways that mediate CCN 1 functions will be identified biochemically and functionally. Third, the tissue specific functions of CCN1 in development will be examined by conditional gene targeting. Through these studies, we hope to gain insight into how CCN1 acts as a matricellular protein to control multiple cellular processes.
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