5-Hydroxytryptamine 2B receptor regulates cell-cycle progression: Cross-talk with tyrosine kinase pathways

Canan G Nebigil (1) , J.-M. Launay (2, 1) , Pierre Hickel (1) , C. Tournois (1, 2) , Luc Maroteaux (1)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 Hôpital Lariboisière-Fernand-Widal [APHP]

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.

Domaines: Biologie moléculaire; Organisation et fonctions cellulaires [q-bio.SC]

Canan G Nebigil, J.-M. Launay, Pierre Hickel, C. Tournois, Luc Maroteaux. 5-Hydroxytryptamine 2B receptor regulates cell-cycle progression: Cross-talk with tyrosine kinase pathways. Proceedings of the National Academy of Sciences of the United States of America, 2000, 97 (6), pp.2591-2596. ⟨10.1073/pnas.050282397⟩. ⟨hal-02926507⟩