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)
- protein kinase A
Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
Present address for N. Dumaz: INSERM U659, 8 rue du Général Sarrail, 94010 Créteil, France.
- Received November 29, 2005.
- Revision received June 12, 2006.
- Accepted July 13, 2006.
- ©2006 American Association for Cancer Research.