| CYR61, an angiogenic factor and a member of the CCN gene family, is an extracellular matrix-associated, heparin-binding protein that mediates cell adhesion and induces cell adhesive signaling, stimulates cell migration, and enhances growth factor stimulated cell proliferation. CYR61 induces angiogenesis and promotes tumor growth in vivo, and is expressed in dermal fibroblasts during cutaneous wound healing. CYR61 is composed of four discrete structural domains that bear sequence similarities to the insulin-like growth factor binding proteins, von Willebrand factor type C repeat, thrombospondin type 1 repeat, and a carboxy-terminal (CT) domain that resembles cysteine knots in some growth factors.; To investigate the structure-function relationship of CYR61, a mutant (CYR61ΔCT) lacking the entire CT domain was constructed. This mutant is unable to support adhesion of primary human skin fibroblasts, but is still able to stimulate chemotaxis and enhance bFGF-induced mitogenesis. Additionally, it was found that CYR61 promotes primary human fibroblast adhesion, migration, and mitogenesis through integrins α6β1, α vβ5, and αvβ3, respectively, with CYR61ΔCT signaling through the same receptors as the wild type protein. Furthermore, CYR61 binds purified integrin αvβ 5 in vitro.; The expression of CYR61 in vascular injury and its action on vascular smooth muscle cells (VSMCs) has also been examined. In a rat carotid artery balloon angioplasty model of vascular wound healing, CYR61 expression is localized to the media and neo-intima of the injured vessel, is elevated by day 4 post-angioplasty, and remains high for at least 28 days. CYR61 supports VSMC adhesion in a dose-dependent, saturable manner through integrin α6β1, with the absolute requirement of cell surface HSPGs, and directed VSMC chemotaxis through integrin α6β1, and HSPGs, with these receptors acting independently.; Together, these data establish that CYR61 interacts with distinct integrins to mediate disparate activities in a cell-type and specific manner, provide support for independent and interdependent domain activity, and suggest a role for CYR61 in modulating VSMC activity during vascular injury. |
