1. ¹Klinik für Dermatologie, Venerologie und Allergologie, Julius-Maximilians-Universität, Würzburg, Germany
2. ²Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Julius-Maximilians-Universität, Würzburg, Germany

Correspondence: Professor Juergen C. Becker, Department of Dermatology, Universitätsklinik Würzburg, Josef-Schneider-Strasse 2, Würzburg 97080, Germany. E-mail: becker_jc@klinik.uni-wuerzburg.de

Received 13 December 2006; Revised 24 December 2007; Accepted 6 January 2008; Published online 6 March 2008.

Abstract

Mutated BRAF and NRAS are suspected to contribute to melanomagenesis by activation of extracellular signal-regulated kinase (ERK). To test this notion, we analyzed the presence of phosphorylated ERK1/2 in 170 melanomas with established NRAS/BRAF mutational status and well-documented clinical follow-up by immunohistochemistry. Several notable observations were obtained: (i) phospho-ERK staining was very heterogeneous within the tumor; (ii) in most cases, ERK was phosphorylated in only a minority of tumor cells; (iii) the percentage of phospho-ERK-positive cells was not correlated with the mutational status of NRAS and/or BRAF; (iv) the Raf kinase inhibitor protein (RKIP) was expressed homogeneously in virtually all melanoma samples not reflecting the inhomogeneity of phospho-ERK; and, finally, (v) neither the portion of phospho-ERK-positive tumor cells nor the RKIP staining intensity showed any correlation to the clinical course of the patients. Furthermore, the ability of BRAF mutant melanoma cells to downregulate mitogen-activated protein kinase activation was shown in melanoma cell lines cultured at high densities or under nonadherent conditions. Our findings suggest that mitogen-activated protein kinase (MAPK) activity is subject to regulation even in BRAF/NRAS mutant melanoma cells and that high MAPK pathway signaling may be important only in distinct subsets of tumor cells.