Figure 2.

CCN1 signaling and crosstalk with TNFα. Signal transduction initiated by CCN1, a prototypical member of the family, is mediated primarily through binding to α₆β₁ and syndecan-4 in fibroblasts to support activities including cell adhesion, although α_vβ₅ is also necessary for fibroblast migration and crosstalk with TNFα (Grzeszkiewicz et al., 2001; Chen et al., 2007). Cell adhesion to CCN1 activates FAK, paxillin, and Rac1, leading to actin cytoskeleton reorganization, cell spreading, and formation of filopodia and lamellipodia (Chen et al., 2001a). Adhesion to CCN1 also induces sustained ERK activation, an activity that is mediated through binding to α₆β₁-HSPG (Leu et al., 2004). CCN1 induces fibroblast apoptosis by activating p53 and Bax (Todorovic et al., 2005), and converts TNFα from a pro-mitogenic factor into a potent apoptotic molecule through the Rac1-dependent generation of ROS via 5-lipoxygenase and the mitochondria (Chen et al., 2007). CCN1/TNFα-induced apoptosis occurs rapidly (within 4 hours of treatment) without requiring de novo protein synthesis, indicating that CCN1 activates this pathway directly.