Absence of classical MAP kinase pathway signalling in Merkel cell carcinoma.
Merkel cell carcinoma (MCC) is a highly metastatic skin tumor. To assess the relevance of the Ras/Raf/MEK/MAP kinase pathway, we analyzed for activating B-Raf mutations and we elucidated the presence of the Raf Kinase Inhibitor Protein (RKIP) and extracellular signal-regulated kinase (ERK) as well as the phosphorylation status of ERK. All MCC samples were negative for the B-Raf(V600E) mutation. Remarkably, RKIP, which was shown to interfere with the activation of MEK by Raf, was highly expressed in primary as well as in metastatic MCC. Immunohistochemical analysis of the phosphorylation status of ERK revealed in 42 out of 44 samples a complete lack of activated ERK in the tumor cells although ERK is expressed; in the two positive cases phosphorylated ERK was restricted to a minor fraction of the tumor cells. Western blot analysis of three MCC-derived cell lines revealed in one case the pattern present in situ (i.e. high RKIP expression and complete absence of phosphorylated ERK). In summary, our data demonstrate the inactivity of the classical MAP kinase signal transduction pathway in MCC, which seems to be because of lack of activation as well as active deactivation. These findings should be accounted for in future therapeutic approaches for this tumor.
Houben
Roland
R
Klinik und Poliklinik für Haut- und Geschlechtskrankheiten, Julius-Maximilians-University Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany. houben_r@klinik.uni-wuerzburg.de
Michel
Barbara
B
Vetter-Kauczok
Claudia S
CS
Pföhler
Claudia
C
Laetsch
Barbara
B
Wolter
Manfred D
MD
Leonard
J Helen
JH
Trefzer
Uwe
U
Ugurel
Selma
S
Schrama
David
D
Becker
Juergen C
JC
D000727:Androgen-Binding Protein / Q000032:analysis; D015266:Carcinoma, Merkel Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009154:Mutation; D049488:Phosphatidylethanolamine Binding Protein; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology
D000727:Androgen-Binding Protein; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases