title: Involvement of Gq/11 in both integrin signal-dependent and -independent pathways regulating endothelin-induced neural progenitor proliferation.
abstract: We have previously shown that endothelin-B receptor stimulation increases neural progenitor proliferation, partly in G(i) and extracellular matrix molecule-dependent manner. In the present study, we investigated whether G(q/11) is also involved in this response and how G(i) and G(q/11) might regulate the extracellular signal-regulated kinase (ERK) pathway and integrin signaling. Endothelin-induced ERK phosphorylation was independent of integrin ligands, and an inhibitor of G(q/11), YM-254890, as well as pertussis toxin, partially inhibited endothelin-stimulated phosphorylation of Raf-1 and ERK. Endothelin-stimulated protein kinase C (PKC) was partially inhibited by both YM-254890 and pertussis toxin, while only pertussis toxin attenuated endothelin-induced Ras activation. In contrast, endothelin increased tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin in an integrin ligand-dependent manner. Both YM-254890 and pertussis toxin partially inhibited endothelin-stimulated phosphorylation of these proteins. A PKC inhibitor and down-regulation of PKC prevented endothelin-induced phosphorylation of paxillin and ERK. In addition, endothelin-induced proliferation and DNA synthesis were partially inhibited by YM-254890 and pertussis toxin. Taken together, the results indicate that endothelin activates PKC via G(q/11) and G(i), and consequently stimulates the ERK cascade in cooperation with Ras signaling stimulated by G(i). PKC appears to increase tyrosine phosphorylation of paxillin to enhance integrin signaling, which further increases DNA synthesis and proliferation.
authors: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kamiya-cho, Kasugai, Aichi 480-0392, Japan.
authors: Rika
authors: R
authors: Morishita
authors: Hiroshi
authors: H
authors: Ueda
authors: Hidenori
authors: H
authors: Ito
authors: Jun
authors: J
authors: Takasaki
authors: Koh-Ichi
authors: K
authors: Nagata
authors: Tomiko
authors: T
authors: Asano
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051419:Paxillin / Q000187:drug effects / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016232:Endothelins; D004791:Enzyme Inhibitors; D016023:Integrins; D051419:Paxillin; D004247:DNA; D037342:Pertussis Toxin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11