5-hydroxytryptamine 2B receptor regulates cell-cycle progression: cross-talk with tyrosine kinase pathways.
In this paper, we present evidence that activation of 5-hydroxytryptamine 2B (5-HT2B) receptors by serotonin (5-HT) leads to cell-cycle progression through retinoblastoma protein hyperphosphorylation and through activation of both cyclin D1/cdk4 and cyclin E/cdk2 kinases by a mechanism that depends on induction of cyclin D1 and cyclin E protein levels. The induction of cyclin D1 expression, but not that of cyclin E, is under mitogen-activated protein kinase (MAPK) control, indicating an independent regulation of these two cyclins in the 5-HT2B receptor mitogenesis. Moreover, by using the specific platelet-derived growth factor receptor (PDGFR) inhibitor AG 1296 or by overexpressing a kinase-mutant PDGFR, we show that PDGFR kinase activity is essential for 5-HT2B-triggered MAPK/cyclin D1, but not cyclin E, signaling pathways. 5-HT2B receptor activation also increases activity of the Src family kinase, c-Src, Fyn, and c-Yes. Strikingly, c-Src, but not Fyn or c-Yes, is the crucial molecule between the G(q) protein-coupled 5-HT2B receptor and the cell-cycle regulators. Inhibition of c-Src activity by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) or depletion of c-Src is sufficient to abolish the 5-HT-induced (i) PDGFR tyrosine kinase phosphorylation and MAPK activation, (ii) cyclin D1 and cyclin E expression levels, and (iii) thymidine incorporation. This paper elucidates a model of 5-HT2B receptor mitogenesis in which c-Src acts alone to control cyclin E induction and in concert with the receptor tyrosine kinase PDGFR to induce cyclin D1 expression via the MAPK/ERK pathway.
Nebigil
C G
CG
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur de Strasbourg, B.P. 163, 67404 Illkirch Cedex, France.
Launay
J M
JM
Hickel
P
P
Tournois
C
C
Maroteaux
L
L
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D044403:Receptor, Serotonin, 5-HT2B; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D011985:Receptors, Serotonin / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
C534703:Ccng1 protein, mouse; D019927:Cyclin E; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D012701:Serotonin; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases