A dual signaling cascade that regulates the ectodomain shedding of heparin-binding epidermal growth factor-like growth factor

Ectodomain shedding is an important mechanism to regulate the biological ac tivities of membrane proteins. We focus here on the signaling mechanism of the ectodomain shedding of heparin-binding epidermal growth factor (EGF)-li ke growth factor (pro HB-EGF). Lysophosphatidic acid (LPA), a ligand for se ven-transmembrane G protein-coupled receptors, stimulates the shedding of p ro HB-EGF, which constitutes a G protein-coupled receptor-mediated transact ivation of the EGF receptor. Experiments using a series of inhibitors and o verexpression of mutant forms of signaling molecules revealed that the Ras- Raf-MEK signal is essential for the LPA-induced shedding. In addition, the small GTPase Rac is involved in the LPA-induced shedding, possibly to promo te MEK activation. 12-O-Tetradecanoylphorbol-13-acetate is another potent i nducer of pro HB-EGF shedding. We also demonstrate that the LPA-induced pat hway is distinct from the 12-O-tetradecanoylphorbol-13-acetate-induced path way and that these pathways constitute a dual signaling cascade that regula tes the shedding of pro HB-EGF.