Mechanism for activation of heparin-binding EGF-like growth factor induced by stimuli

Abstract

Heparin-binding epidermal growth factor-like growth factor(HB-EGF), which belongs to the EGF family, is a critical growth factor for a number of physiological and pathological processes, such as wound healing and cardiac hypertrophy. HB-EGF is synthesized as a membrane-anchored form(pro-HB-EGF), and pro-HB-EGF is cleaved at the cell surface to yield soluble HB-EGF by a mechanism called "ectodomain shedding". Soluble HB-EGF has mitogenic activity. Ectodomain shedding of proHB-EGF is induced by stimuli, including 12-O-tetradecanoylphorbol-13-acetate(TPA), a ligand for seven-transmembrane G protein-coupled receptors(GPCR), stress and inflammatory cytokine. Lysophosphatidic acid(LPA), a ligand for GPCR, stimulates the shedding of proHB-EGF, which constitutes a GPCR-mediated transactivation of the EGF receptor. Ras-Raf-MEK signal and the small GTPase Rac are essential for the LPA-induced shedding. On the other hand, protein kinase C and ADAM 9 protease are essential for the TPA-induced shedding. Furthermore, p38 MAPK is essential for the stress- and IL-1 beta-induced shedding. Finally there is a mechanism for activation of HB-EGF regulated by the environment in the living body.