Cyr61, a Product of a Growth Factor-Inducible Immediate-Early Gene, Promotes Cell Proliferation, Migration, and Adhesion

Abstract

cyr61 was first identified as a growth factor-inducible immediate-early gene in mouse fibroblasts. The encoded Cyr61 protein is a secreted, cystein-rich heparin-binding protein that associates with the cell surface and the extracellular matrix, and in these aspects it resembles the Wnt-1 protein and a number of known growth factors. During embryogenesis, cyr61 is expressed most notably in mesenchymal cells that are differentiating into chondrocytes and in the vessel walls of the developing circulatory system. cyr61 is a member of an emerging gene family that encodes growth regulators, including the connective tissue growth factor and an avian proto-oncoprotein, Nov cyr61 also shares sequence similarities with two Drosophila genes, twisted gastrulation and short gastrulation, which interact with decapentaplegic to regulate dorsal-ventral patterning. In this report we describe the purification of the Cyr61 protein in a biologically active form, and we show that purified Cyr61 has the following activities: (i) it promotes the attachment and spreading of endothelial cells in a manner similar to that of fibronectin; (ii) it enhances the effects of basic fibroblast growth factor and platelet-derived growth factor on the rate of DNA synthesis of fibroblasts and vascular endothelial cells, although it has no detectable mitogenic activity by itself; and (iii) it acts as a chemotactic factor for fibroblasts. Taken together, these activities indicate that Cyr61 is likely to function as an extracellular matrix signaling molecule rather than as a classical growth factor and may regulate processes of cell proliferation, migration, adhesion, and differentiation during development.

Human CYR61-mediated enhancement of bFGF-induced DNA synthesis in human umbilical vein endothelial cells

“…The functions of CYR61, and perhaps those of members of the protein family, may act to help mediate the cellular responses of the growth factors that induce CYR61 synthesis. Consistent with this hypothesis, our laboratory has detected several activities of CYR61: it promotes cell adhesion, stimulates chemotaxis, and augments growth factor-induced DNA synthesis (Kireeva et al, 1996(Kireeva et al, , 1997. a b Figure 6 hCYR61 displacement of bFGF from the ECM to enhance DNA synthesis.…”

“…While the murine mCyr61 has no detectable mitogenic activity by itself, it enhances bFGF-induced DNA synthesis in both HUVECs and ®broblasts (Kireeva et al, 1996(Kireeva et al, , 1997. Likewise, we found that the recombinant hCYR61 protein alone did not stimulate [ 3 H]thymidine incorporation in HUVECs, but was able to enhance bFGF-induced DNA synthesis in a manner similar to that of the mouse homolog ( Figure 3).…”

“…Cyr61 also induces chemotaxis in ®broblasts (Kireeva et al, 1996), and enhances growth factor-stimulated DNA synthesis in both ®broblasts and endothelial cells (Kireeva et al, 1996(Kireeva et al, , 1997. These activites suggest that Cyr61 may act as a mediator of growth factors that stimulate its synthesis, thereby modulating cellular processes that involve cell adhesion, migration, and proliferation.…”

“…Likewise, we found that the recombinant hCYR61 protein alone did not stimulate [ 3 H]thymidine incorporation in HUVECs, but was able to enhance bFGF-induced DNA synthesis in a manner similar to that of the mouse homolog ( Figure 3). This e ect is inhibitable by neutralizing anti-Cyr61 antibody but not by preimmune serum or unrelated antibodies (Kireeva et al, 1996(Kireeva et al, , 1997 and can be attributable to hCYR61 ( Figure 3). While these experiments were carried out in F12 medium, we observed that the bFGF-and hCYR61-dependencies of DNA synthesis of HUVECs in Endothelial Serum-Free Medium (Endo-SFM) were somewhat di erent.…”

“…Puri®ed recombinant murine Cyr61 mediates cell adhesion for ®broblasts, endothelial cells, and epithelial cells (Kireeva et al, 1996(Kireeva et al, , 1997. Cyr61 also induces chemotaxis in ®broblasts (Kireeva et al, 1996), and enhances growth factor-stimulated DNA synthesis in both ®broblasts and endothelial cells (Kireeva et al, 1996(Kireeva et al, , 1997.…”