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ERK and PDE4 cooperate to induce RAF isoform switching in melanoma

Nature Structural & Molecular Biology volume 18, pages 584–591 (2011)Cite this article

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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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Figure 1: NRAS G12V is oncogenic in melanocytes and induces Raf isoform switching.
Figure 2: Mek inhibition rescues NRAS-BRAF binding in melanoma.
Figure 3: BRAF is phosphorylated on Ser151.
Figure 4: Disruption of the cAMP pathway in melanoma.
Figure 5: Increased PDE4 activity in melanoma compared with melanocytes.
Figure 6: Increased PDE4B2 expression in melanoma compared with melanocytes.
Figure 7: Reactivation of the cAMP pathway in melanoma inhibits the MAPK pathway and induces apoptosis.

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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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Authors and Affiliations

  1. INSERM U976, Hôpital Saint Louis, Paris, France

    Amélie Marquette, Jocelyne André, Martine Bagot, Armand Bensussan & Nicolas Dumaz

  2. Université Paris 7–Denis Diderot, Hôpital Saint Louis, Paris, France

    Amélie Marquette, Jocelyne André, Martine Bagot, Armand Bensussan & Nicolas Dumaz

  3. Department of Dermatology, Assistance Public—Hôpitaux de Paris, Hôpital Saint Louis, Paris, France

    Martine Bagot & Armand Bensussan

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  1. Amélie Marquette
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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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Correspondence to Nicolas Dumaz.

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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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