Abstract
Melanocytes use BRAF to activate the MAP kinase (MAPK) pathway because CRAF is inhibited by the cyclic AMP (cAMP) pathway in these cells. By contrast, melanomas harboring Ras mutations use CRAF to activate the MAPK pathway. We describe the molecular mechanism of Raf isoform switching and cAMP pathway disruption, which take place during melanocyte transformation. We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction . We also demonstrate that melanoma cells have elevated cAMP phosphodiesterase activity owing to overexpression of the cAMP-specific phosphodiesterase-4 enzymes; this activity inhibits cAMP signaling and allows CRAF reactivation in these cells. Reactivating the cAMP pathway inhibits proliferation and induces apoptosis of Ras-mutated melanoma cells, suggesting a new therapeutic approach for treating melanomas harboring Ras mutations.
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Acknowledgements
We thank M.D. Houslay (University of Glasgow, Glasgow, UK) for the PDE4B antibody and the PDE4D constructs, G. Cosler for technical help and K. Dumaz for proofreading the manuscript. This work was funded by the French Institut National de la Santé et de la Recherche Médicale, Université Paris VII, Société Française de Dermatologie, Ligue Contre le Cancer (Comité du Val de Marne) and the French Institut National du Cancer (INCa 2007-1-PL7).
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A.M., J.A. and N.D. carried out research; M.B., A.B. and N.D. designed and directed the project; N.D. wrote the paper.
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Marquette, A., André, J., Bagot, M. et al. ERK and PDE4 cooperate to induce RAF isoform switching in melanoma. Nat Struct Mol Biol 18, 584–591 (2011). https://doi.org/10.1038/nsmb.2022
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DOI: https://doi.org/10.1038/nsmb.2022
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