c-Src is activated by the epidermal growth factor receptor in a pathway that mediates JNK and ERK activation by gonadotropin-releasing hormone in COS7 cells.
Key participants in G protein-coupled receptor (GPCR) signaling are the mitogen-activated protein kinase (MAPK) signaling cascades. The mechanisms involved in the activation of the above cascades by GPCRs are not fully elucidated. A prototypic GPCR that has been widely used to study these signaling mechanisms is the receptor for gonadotropin-releasing hormone (GnRHR), which serves as a key regulator of the reproductive system. Here we expressed GnRHR in COS7 cells and found that GnRHR transmits its signals to MAPKs mainly via G alpha i, EGF receptor without the involvement of Hb-EGF, and c-Src, but independently of PKCs. The main pathway that leads to JNK activation downstream of the EGF receptor involves a sequential activation of c-Src and phosphatidylinositol 3-kinase (PI3K). ERK activation by GnRHR is mediated by the EGF receptor, which activates Ras either directly or via c-Src. Besides the main pathway, the dissociated G beta gamma and beta-arrestin may initiate additional, albeit minor, pathways that lead to MAPK activation in the transfected COS7 cells. The pathways detected are significantly different from those in other cell lines bearing GnRHR, indicating that GnRH can utilize various signaling mechanisms for the activation of MAPK cascades. The unique pathway elucidated here in which c-Src and PI3K are sequentially activated downstream of the EGF receptor may serve as a prototype of signaling mechanisms by GnRHR and by additional GPCRs in various cell types.
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Sarah
S
Kraus
Outhiriaradjou
O
Benard
Zvi
Z
Naor
Rony
R
Seger
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D015153:Blotting, Western; D019556:COS Cells; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism* / Q000502:physiology*; D011966:Receptors, LHRH / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D000071557:beta-Arrestins; D018631:ras Proteins / Q000378:metabolism
D019390:Arrestins; D011966:Receptors, LHRH; D000071557:beta-Arrestins; D007987:Gonadotropin-Releasing Hormone; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020962:Heterotrimeric GTP-Binding Proteins; D018631:ras Proteins