Proteolytic cleavage of epidermal growth factor receptor by caspases

Apoptotic proteases cleave and inactivate survival signaling molecules such as Akt/PKB, phospholipase C (PLC)-gamma1, and Bcl-2. We have found that tr eatment of A431 cells with tumor necrosis factor-alpha in the presence of c ycloheximide resulted in the cleavage of epidermal growth factor receptor ( EGFR) as well as the activation of caspase-3. Among various caspases, caspa se-1, caspase-3 and caspase-7 were most potent in the cleavage of EGFR in v itro. Proteolytic cleavage of EGFR was inhibited by both YVAD-cmk and DEVD- fmk in vitro. We also investigated the effect of caspase-dependent cleavage of EGFR upon the mediation of signals to downstream signaling molecules su ch as PLC-gamma1. Cleavage of EGFR by caspase-3 significantly impaired the tyrosine phosphorylation of PLC-gamma1 in vitro. Given these results, we su ggest that apoptotic protease specifically cleaves and inactivates EGFR, wh ich plays crucial roles in anti-apoptotic signaling, to abrogate the activa tion of EGFR-dependent downstream survival signaling molecules, (C) 2001 Fe deration of European Biochemical Societies. Published by Elsevier Science B .V. All rights reserved.