In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling.
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.
Dumaz
Nicolas
N
Signal Transduction Team, The Institute for Cancer Research, Cancer Research UK Centre of Cell and Molecular Biology, London, United Kingdom.
Hayward
Robert
R
Martin
Jan
J
Ogilvie
Lesley
L
Hedley
Douglas
D
Curtin
John A
JA
Bastian
Boris C
BC
Springer
Caroline
C
Marais
Richard
R
D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D011905:Genes, ras; D006801:Humans; D008544:Melanocytes / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009363:Neoplasm Proteins / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000521:alpha-MSH / Q000494:pharmacology
D009363:Neoplasm Proteins; D000521:alpha-MSH; D000242:Cyclic AMP; C482119:BRAF protein, human; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate