| The CCN family protein Cyr61 is an extracellular matrix-associated heparin-binding protein that can induce angiogenesis and promote chondrogenesis in vivo. Encoded by an immediate-early gene, Cyr61 is shown in this study as an indispensable mediator of growth factor induced gene expression. Among the genes whose induction by growth factors is mediated by Cyr61 are key regulators of angiogenesis and tissue remodeling such as VEGF-A, TIMPs, and PAI-1. Cyr61 also mediates TGF-β1 induced proteoglycan expression. These observations suggest possible mechanisms of how Cyr61 may function during development, wound healing, and tumorigenesis. Expression of ctgf , a closely related CCN family member, was found upregulated in cyr61-null fibroblasts, which indicates possible compensation by CTGF during the development of cyr61 knockout embryos.; Previous studies demonstrated that Cyr61 mediates adhesion of vascular endothelial cells and platelets through integrins αVβ 3 and αIIbβ3, respectively. In this study, we show that the adhesion of primary human skin fibroblasts to Cyr61 is mediated through integrin α6β1 and cell surface heparan sulfate proteoglycans. Using domain-specific antibodies, we located the possible integrin α6β1 binding site to the TSP domain and the integrin αVβ5 binding site to the VWC domain. Consistent with the fact that Cyr61 is an ECM molecule with high affinity to heparin, preliminary studies indicate that integrin α6β1 and HSPGs could be the receptors which transduce the Cyr61 signaling in regulating these gene expression. |
