Phospho-ERK staining is a poor indicator of the mutational status of BRAF and NRAS in human melanoma

J Invest Dermatol. 2008 Aug;128(8):2003-12. doi: 10.1038/jid.2008.30. Epub 2008 Mar 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mutation / genetics*
  • Phosphatidylethanolamine Binding Protein / metabolism
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Signal Transduction / genetics
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology


  • PEBP1 protein, human
  • Phosphatidylethanolamine Binding Protein
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Extracellular Signal-Regulated MAP Kinases
  • Proto-Oncogene Proteins p21(ras)