Signaling of intermediate cell adhesion: role in tissue remodeling

The matricellular proteins thrombospondins (TSP) 1 and 2, tenascin‐C, and SPARC signal cytoskeletal reorganization of adherent cells. Each signals via distinct receptors, but induces a common adhesive phenotype known as intermediate adhesion, characterized by restructuring of focal adhesions, loss of stress fibers, with maintenance of spread cell shape and integrin clustering. TSP1 signals intermediate cell adhesion through binding of a sequence in its N‐terminus to a receptor co‐complex of calreticulin and LRP1 localized to lipid rafts. TSP1 signaling through calreticulin‐LRP1 activates PI3K, FAK, ERK, src, and downregulates Rho activity. TSP1 induction of intermediate cell adhesion increases random and directed cell motility of fibroblasts and endothelial cells. These effects can be mimicked by a peptide (hep I) comprising this sequence of TSP1. TSP1 signaling through its hep I sequence also activates the anti‐apoptotic signal Akt and reduces apoptotic cell death under anoikis‐promoting conditions. More recent work has addressed the role of hep I signaling in wound healing in a subcutaneous sponge model of the foreign body response. These studies show that impregnation of sponges with plasmid expressing the hep I sequence, but not a control sequence, alters the foreign body response. These studies suggest that matricellular signaling of intermediate cell adhesion is important for tissue remodeling.