Ras involvement in signal transduction by the serotonin 5-HT2B receptor.
The family of serotonin 5-HT2 receptors stimulates the phospholipase C second messenger pathway via the alpha subunit of the Gq GTP-binding protein. Here, we show that agonist stimulation of the 5-HT2B receptor subtype stably expressed in the mouse fibroblast LMTK- cell line causes a rapid and transient activation of the proto-oncogene product p21ras as measured by an increase in GTP-bound Ras in response to serotonin. Furthermore, 5-HT2B receptor stimulation activates p42mapk/p44mapk (ERK2/ERK1) mitogen-activated protein kinases as assayed by phosphorylation of myelin basic protein. Antibodies against p21ras, Galphaq, -beta, or -gamma2 subunits of the GTP-binding protein inhibit MAP kinase-dependent phosphorylation. The MAP kinase activation is correlated with a stimulation of cell division by serotonin. In addition to this mitogenic action, transforming activity of serotonin is mediated by the 5-HT2B receptor since its expression in LMTK- cells is absolutely required for foci formation and for these foci to form tumors in nude mice. Finally, we detected expression of the 5-HT2B receptor in spontaneous human and Mastomys natalensis carcinoid tumors and, similar to the 5-HT2B receptor transfected cells, the Mastomys tumor cells are also responsive to serotonin with similar coupling to p21ras activation.
Launay
J M
JM
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université L. Pasteur de Strasbourg, CNRS, INSERM, BP 163-67404 Illkirch Cedex, France.
Birraux
G
G
Bondoux
D
D
Callebert
J
J
Choi
D S
DS
Loric
S
S
Maroteaux
L
L
D000662:Amphetamines / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002276:Carcinoid Tumor / Q000378:metabolism* / Q000473:pathology / Q000662:veterinary; D002460:Cell Line; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D051379:Mice; D009115:Muridae; D000090063:Proto-Oncogene Mas; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D016713:Ritanserin / Q000494:pharmacology; D012376:Rodent Diseases; D015290:Second Messenger Systems; D012701:Serotonin / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism; D018631:ras Proteins
D000662:Amphetamines; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; D016713:Ritanserin; D012701:Serotonin; D010738:Type C Phospholipases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D018631:ras Proteins; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine