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In Melanoma, RAS Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling

¹ Signal Transduction Team, The Institute for Cancer Research, Cancer Research UK Centre of Cell and Molecular Biology, London, United Kingdom, ² Gene and Oncogene Targeting Team, Cancer Research UK Centre for Cancer Therapeutics, Sutton, United Kingdom; and ³ Departments of Dermatology and Pathology and Comprehensive Cancer, University of California San Francisco, San Francisco, California

Requests for reprints: Richard Marais, Signal Transduction Team, The Institute of Cancer Research, Cancer Research UK Centre for Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, United Kingdom. Phone: 44-20-7878-3856; Fax: 44-20-7878-3856; E-mail: richard.marais{at}icr.ac.uk.

Melanocytes require the RAS/RAF/MEK/ERK and the cyclic AMP (cAMP) signaling pathways to maintain the fine balance between proliferation and differentiation. We have investigated how cross-talk between these pathways affects melanoma progression. We show that cAMP suppresses CRAF activity in melanocytes and that this is essential to suppress the oncogenic potential of CRAF in these cells. As a consequence, BRAF alone is responsible for signaling to MEK. However, when RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF. This switch is accompanied by dysregulated cAMP signaling, a step that is necessary to allow CRAF to signal to MEK. Thus, a fundamental switch in RAF isoform usage occurs when RAS is mutated in melanoma, and this occurs in the context of disrupted cAMP signaling. These data have important implications for the development of therapeutic strategies to treat this life-threatening disease. (Cancer Res 2006; 66(19): 9483-91)

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