Role of dynamin, Src, and Ras in the protein kinase C-mediated activation of ERK by gonadotropin-releasing hormone.
G-protein-coupled receptors are a large group of integral membranal receptors, which in response to ligand binding initiate diverse downstream signaling. Here we studied the gonadotropin-releasing hormone (GnRH) receptor, which uses Gq for its downstream signaling. We show that extracellular signal-regulated kinase (ERK) activation is fully dependent on protein kinase C (PKC), but only partially dependent on Src, dynamin, and Ras. Receptor tyrosine kinases, FAK, Gbetagamma, and beta-arrestin, which were implicated in some G-protein-coupled receptor signaling to MAPK cascades, do not play a role in the GnRH to ERK pathway. Our results suggest that the activation of ERK by GnRH involves two distinct signaling pathways, which converge at the level of Raf-1. The main pathway involves a direct activation of Raf-1 by PKC, and this step is partially dependent on a second pathway consisting of Ras activation, which occurs in a dynamin-dependent manner, downstream of Src.
Benard
O
O
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Naor
Z
Z
Seger
R
R
D000818:Animals; D019390:Arrestins / Q000502:physiology; D002460:Cell Line; D034281:Dynamins; D066246:ErbB Receptors / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020558:GTP Phosphohydrolases / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D008954:Models, Biological; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology*; D000071557:beta-Arrestins
D019390:Arrestins; D000071557:beta-Arrestins; D007987:Gonadotropin-Releasing Hormone; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D020558:GTP Phosphohydrolases; D020962:Heterotrimeric GTP-Binding Proteins; D016283:Proto-Oncogene Proteins p21(ras); D034281:Dynamins