Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation.
Dysregulated activation of Ras or its downstream effectors such as mitogen-activated protein kinase kinase and ERK has been shown to play a critical role in tumorigenesis of many cancer types. However, in melanoma, activating mutations in Ras are rarely observed and are limited to N-Ras in UV-exposed cells. In this study, we identify constitutively activated ERK in almost all melanoma cell lines and in tumor tissues tested, which is in contrast to normal melanocytes and several early stage radial growth phase melanoma lines where ERK can be activated by serum or growth factors. Constitutive activation of ERK is preceded by phosphorylation of mitogen-activated protein kinase kinase and c-RAF. In all of the melanoma cell lines tested, Ras is constitutively activated without underlying mutations. On the contrary, activating mutations in the kinase domain of BRAF are present in the majority of the cell lines tested. Furthermore, ERK activation can be partially inhibited from the cell surface using inhibitors of fibroblast growth factor and hepatocyte growth factor but not interleukin 8 signaling pathways. These data suggest that melanoma growth, invasion, and metastasis are attributable to constitutively activated ERK apparently mediated by excessive growth factors through autocrine mechanisms and BRAF kinase activation.
Satyamoorthy
Kapaettu
K
Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Li
Gang
G
Gerrero
Michelle R
MR
Brose
Marcia S
MS
Volpe
Patricia
P
Weber
Barbara L
BL
Van Belle
Patricia
P
Elder
David E
DE
Herlyn
Meenhard
M
D004789:Enzyme Activation; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000502:physiology; D006133:Growth Substances / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000502:physiology; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D014407:Tumor Cells, Cultured
D006133:Growth Substances; D016209:Interleukin-8; D005346:Fibroblast Growth Factors; D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human