Intracellular Signaling Mechanisms Leading to Synergistic Effects of Endothelin-1 and Stem Cell Factor on Proliferation of Cultured Human Melanocytes CROSS-TALK VIA TRANS-ACTIVATION OF THE TYROSINE KINASE c-KIT RECEPTOR

摘要: Abstract We previously reported that activation of mitogen-activated protein kinase (MAPK) is involved in the mitogenic stimulation normal human melanocytes (NHMC) by endothelin-1 (ET-1). In present study, we determined signaling mechanisms upstream MAPK are ET-1 and their synergism with stem cell factor (SCF). Pretreatment cultured NHMC ETB receptor antagonists, pertussis toxin, a specific phospholipase C inhibitor (U73122), or (calphostine) blocked transient tyrosine phosphorylation induced ET-1, whereas addition calcium chelator (BAPTA) failed to inhibit MAPK. Treatment SCF together synergistically increased DNA synthesis, which was accompanied for phosphorylation. The time course inositol 1,4,5-trisphosphate formation revealed there no difference level stimulated + alone. Evaluations serine MEK Raf-1 activity showed synergistic effect ET-1-treated NHMC. Stimulation more rapid stronger tyrosyl proteins corresponding p52 p66 Shc than did only, this association tyrosine-phosphorylated Grb2. Interestingly, marked c-kit also detected NHMC-treated treated only. These data indicate cross-talk between initiated through pathway c-kit, results enhanced Shc-Grb2 complex leads turn Ras/Raf-1/MEK/MAP loop.