CCN1/CYR61: the very model of a modern matricellular protein

Abstract

CCN1 (CYR61) is a dynamically expressed, multifunctional matricellular protein that plays essential roles in cardiovascular development during embryogenesis, and regulates inflammation, wound healing and fibrogenesis in the adult. Aberrant CCN1 expression is associated with myriad pathologies, including various cancers and diseases associated with chronic inflammation. CCN1 promotes diverse and sometimes opposing cellular responses, which can be ascribed, as least in part, to disparate activities mediated through its direct binding to distinct integrins in different cell types and contexts. Accordingly, CCN1 promotes cell proliferation, survival and angiogenesis by binding to integrin α(v)β(3), and induces apoptosis and senescence through integrin α(6)β(1) and heparan sulfate proteoglycans. The ability of CCN1 to trigger the accumulation of a robust and sustained level of reactive oxygen species underlies some of its unique activities as a matrix cell-adhesion molecule. Emerging studies suggest that CCN1 might be useful as a biomarker or therapeutic target in certain diseases.

Fig. 1

Schematic diagram of CCN1, its receptor-binding sites, and biological activities. The modular domain structure of CCN1 and the locations of several identified integrin-binding sites are illustrated. The interaction of CCN1 with α_vβ₃ in endothelial cells is critical for its angiogenic activities, which underlie biological functions in embryonic development, cell proliferation, and tumor growth. The interaction of CCN1 with α₆β₁-heparan sulfate proteoglycans (HSPGs) in fibroblasts induces apoptosis or cellular senescence, and may function to regulate the inflammatory response, control fibrosis during wound healing, and suppress tumorigenesis. TBD to be determined

Fig. 2

Signaling pathways mediated through CCN1-induced ROS accumulation. The interaction of CCN1 with α₆β₁ and HSPGs (syndecan-4) is required to trigger the RAC-1-dependent accumulation of ROS through several pathways, including 5-lipoxygenase (5-LOX), NADPH oxidase, and the mitochondria. Neutral sphingomyelinase (nSMase) also contributes to CCN1-induced ROS. CCN1-induced ROS lead to the biphasic activation of JNK, allowing TNF-α to induce apoptosis by targeting c-FLIP for degradation. The high and sustained level of ROS induced by CCN1 also triggers a DNA damage response, leading to p53 activation. ROS also lead to the hyperactivation of ERK and p38 MAPK, which in turn induce p16^INK4a and activate pRb. Both p53 and p16^INK4a/pRb contribute to senescence

Fig. 3

CCN1 controls fibrosis in wound healing by inducing cellular senescence. In cutaneous wound healing, myofibroblasts are recruited to form the granulation tissue, where they proliferate and rapidly synthesize ECM to provide tissue integrity during repair. At later stages of wound healing, these myofibroblasts are driven into senescence by CCN1, whereupon they express an ECM-degrading phenotype and limit fibrosis. Thus, CCN1 functions as an anti-fibrotic molecular switch that converts ECM-producing myofibroblasts into ECM-degrading senescent cells, thereby imposing a self-limiting control on fibrogenesis during wound healing