RGD peptides released from βig-h3, a TGF-β-induced cell-adhesive molecule, mediate apoptosis

betaig-h3 is a transforming growth factor-beta (TGF-beta)-induced cell-adhesive molecule and has an RGD sequence at its C-terminus. A previous report suggested that betaig-h3 normally undergoes carboxy-terminal processing that results in the loss of the RGD sequence. RGD peptides appear to play various roles in cell function. Here we show that the RGD peptides released from betaig-h3 may facilitate TGF-beta-induced apoptosis. We found that carboxy-terminal cleavage of betaig-h3 occurred after its secretion, and that overexpression of the wild-type betaig-h3 induced apoptosis, unlike the C-terminal deleted but RGD-containing mutant betaig-h3, which is resistant to C-terminal processing. The betaig-h3-induced apoptosis was abolished by either deletion of the RGD sequence or mutation of RGD to RAE. Synthetic peptides of ERGDEL and GRGDSP derived from betaig-h3 and fibronectin, respectively, also induced apoptosis, unlike ERGEEL and GRGESP. Culture supernatants of cells overexpressing betaig-h3 filtered to isolate molecules smaller than 3 kDa also induced apoptosis. A fusion protein composed of the N-terminal 100 amino acids of fibronectin and the RGD-containing C-terminal part of betaig-h3 was also subjected to C-terminal cleavage and overexpression resulted in apoptosis. The anti-betaig-h3 antibody blocks TGF-beta-induced apoptosis. Thus, betaig-h3 may be important in regulating cell apoptosis by providing soluble RGD peptides.