Publications de l’équipe
Signalisation Raf et Maf dans l’oncogenèse et le développement
Année de publication : 2003
Hicham Lahlou, Nathalie Saint-Laurent, Jean-Pierre Estève, Alain Eychène, Lucien Pradayrol,
Stéphane Pyronnet, Christiane Susini (2003 Jul 25) sst2 Somatostatin receptor inhibits cell proliferation through Ras-, Rap1-, and
B-Raf-dependent ERK2 activation.
The Journal of biological chemistry : 39356-71
Résumé
The G protein-coupled sst2 somatostatin receptor is a critical negative regulator of cell proliferation. sstII prevents growth factor-induced cell proliferation through activation of the tyrosine phosphatase SHP-1 leading to induction of the cyclin-dependent kinase inhibitor p27Kip1. Here, we investigate the signaling molecules linking sst2 to p27Kip1. In Chinese hamster ovary-DG-44 cells stably expressing sst2 (CHO/sst2), the somatostatin analogue
RC-160 transiently stimulates ERK2 activity and potentiates insulin-stimulated ERK2 activity.
RC-160 also stimulates ERK2 activity in pancreatic acini isolated from normal mice, which endogenously express sst2, but has no effect in pancreatic acini derived from sst2 knock-out mice. RC-160-induced p27Kip1 up-regulation and inhibition of insulin-dependent cell proliferation are both prevented by pretreatment of CHO/sst2 cells with the MEK1/2 inhibitor
PD98059. In addition, using dominant negative mutants, we show that sst2-mediated ERK2 stimulation is dependent on the pertussis toxin-sensitive Gi/o protein, the tyrosine kinase
Src, both small G proteins Ras and Rap1, and the MEK kinase B-Raf but is independent of
Raf-1. Phosphatidylinositol 3-kinase (PI3K) and both tyrosine phosphatases, SHP-1 and
SHP-2, are required upstream of Ras and Rap1. Taken together, our results identify a novel mechanism whereby a Gi/o protein-coupled receptor inhibits cell proliferation by stimulating
ERK signaling via a SHP-1-SHP-2-PI3K/Ras-Rap1/B-Raf/MEK pathway.
Année de publication : 2002
Anne Galy, Bertrand Néron, Nathalie Planque, Simon Saule, Alain Eychène (2002 Aug 9)
Activated MAPK/ERK kinase (MEK-1) induces transdifferentiation of pigmented epithelium into neural retina.
Developmental biology : 251-64
Résumé
During vertebrate eye development, the optic vesicle originating from the neuroectoderm is partitioned into a domain that will give rise to the neural retina (NR) and another that will give rise to the retinal pigmented epithelium (RPE). Previous studies have shown that ectopic expression of FGFs in the RPE induces RPE-to-NR transdifferentiation. Similarly, a naturally occurring mutation of the transcription factor Mitf in mouse resulted in the formation of a second neural retina in place of the dorsal RPE, but the putative signaling pathway linking
FGF to Mitf regulation is presently unknown. In cultures of neural crest-derived melanocytes, the MAPK pathway was recently shown to target the Mitf transcription factor for ubiquitin-

Publications de l’équipe
Signalisation Raf et Maf dans l’oncogenèse et le développement dependent proteolysis, resulting in a rapid degradation and downregulation. In the present study, we show that ectopic expression of a constitutively activated allele of MEK-1, the immediate upstream activator of the MAPK ERK, in chicken embryonic retina in ovo, induces transdifferentiation of the RPE into a neural-like epithelium that is correlated with a downregulation of Mitf expression in the presumptive RPE.
Année de publication : 2001
C Peyssonnaux, A Eychène (2001 Dec 4)
The Raf/MEK/ERK pathway: new concepts of activation.
Biology of the cell / under the auspices of the European Cell Biology Organization : 53-62
Résumé
The Raf/MEK/ERK signaling was the first MAP kinase cascade to be characterized. It is probably one of the most well known signal transduction pathways among biologists because of its implication in a wide variety of cellular functions as diverse -and occasionally contradictory- as cell proliferation, cell-cycle arrest, terminal differentiation and apoptosis.
Discovery and understanding of this pathway have benefited from the combination of both genetic studies in worms and flies and biochemical studies in mammalian cells. However, ten years after, this field is still under debate and new molecular partners in the cascade continue to increase the complexity of its regulation. This review deals with the emergence of new concepts in the activation and regulation of the Raf/MEK/ERK module. In particular, the preponderant role of B-Raf is underlined, and the role of novel regulators such as KSR is discussed.
S Benkhelifa, S Provot, E Nabais, A Eychène, G Calothy, M P Felder-Schmittbuhl (2001 Jun 21)
Phosphorylation of MafA is essential for its transcriptional and biological properties.
Molecular and cellular biology : 4441-52
Résumé
We previously described the identification of quail MafA, a novel transcription factor of the
Maf bZIP (basic region leucine zipper) family, expressed in the differentiating neuroretina
(NR). In the present study, we provide the first evidence that MafA is phosphorylated and that its biological properties strongly rely upon phosphorylation of serines 14 and 65, two residues located in the transcriptional activating domain within a consensus for phosphorylation by mitogen-activated protein kinases and which are conserved among Maf proteins. These residues are phosphorylated by ERK2 but not by p38, JNK, and ERK5 in vitro.
However, the contribution of the MEK/ERK pathway to MafA phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs MafA capacity to activate transcription. Furthermore, we show that the MafA S14A/S65A mutant

Publications de l’équipe
Signalisation Raf et Maf dans l’oncogenèse et le développement displays reduced capacity to induce expression of QR1, an NR-specific target of Maf proteins.
Likewise, the integrity of serines 14 and 65 is essential for the MafA ability to stimulate expression of crystallin genes in NR cells and to induce NR-to-lens transdifferentiation. Thus, the MafA capacity to induce differentiation programs is dependent on its phosphorylation.