Roland Houben, Claudia S. Vetter-Kauczok, Sonja Ortmann, Ulf R

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Phospho-ERK Staining Is a Poor Indicator of the Mutational Status of BRAF and NRAS in Human Melanoma Roland Houben, Claudia S. Vetter-Kauczok, Sonja Ortmann, Ulf R. Rapp, Eva B. Broecker, Juergen C. Becker Journal of Investigative Dermatology Volume 128, Issue 8, Pages 2003-2012 (August 2008) DOI: 10.1038/jid.2008.30 Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 ERK phosphorylation and RKIP expression in melanoma. (a–e) The micrographs show immunohistochemistry for ERK phosphorylated at residues Thr202 and Tyr204 using the antibody (Ab) clone 20G11. (f–i) Phospho-ERK was detected by the use of the Ab clone E10. (j) Total ERK staining and (k and l) RKIP expression. Journal of Investigative Dermatology 2008 128, 2003-2012DOI: (10.1038/jid.2008.30) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 The proportion of phospho-ERK-positive cells does not correlate with the presence of NRAS and BRAF mutations. Box and whiskers plot correlating the phospho-ERK phenotype with the NRAS/BRAF genotype. The percentage of phospho-ERK-positive cells was evaluated and classified as described under Materials and Methods. In the upper part, the mut group, which contains all tumors with validated NRAS or BRAF mutation, is compared with BRAF/NRAS wt tumors, whereas in the lower part, the mut (BRAF) group contains all tumors with validated BRAF mutation and is compared with the tumors without BRAF mutation. On the left, the results obtained with the antibody (Ab) E10 are depicted, whereas in the diagrams on the right, the Ab 20G11 was used. The numbers of analyzed individual tumors in each group are indicated. Journal of Investigative Dermatology 2008 128, 2003-2012DOI: (10.1038/jid.2008.30) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 ERK phosphorylation is still subject to regulation in BRAF mutant melanoma cell lines and the majority of phospho-ERK is in the cytoplasm. (a) ERK phosphorylation is inhibited at high cell densities. The indicated BRAF mutant cell lines were seeded in 12-well plates with the indicated cell numbers and harvested 24hours later. Cell lysates were analyzed for the presence of phosphorylated ERK protein by Western blot. β-Tubulin served as a loading control. (b) ERK phosphorylation depends on cell adherence. The BRAF mutant melanoma cell lines were cultured either in standard tissue culture plates or in ultralow attachment plates in which adherence is inhibited by a hydrophilic, neutrally charged hydrogel layer. (c) Cytoplasmic and nuclear fractions of lysates of the indicated melanoma cell lines were analyzed for the presence of phospho-ERK. Histone H3 served as nuclear marker protein. Journal of Investigative Dermatology 2008 128, 2003-2012DOI: (10.1038/jid.2008.30) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Increased levels of RKIP expression correlate with the proportion of phospho-ERK-positive tumor cells. The intensity of RKIP staining was evaluated as dim, standard, or bright. (a) Distribution of tumor sections with differential RKIP expression in primary (n=98) and metastatic melanoma (n=82). (b) Correlation of the RKIP staining intensity with the percentage of tumor that stained positive for phosphorylation of ERK. The correlation is statistically significant with P=0.0107 in the Kruskal–Wallis test. Journal of Investigative Dermatology 2008 128, 2003-2012DOI: (10.1038/jid.2008.30) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Correlation of phospho-ERK and RKIP status with overall survival. Kaplan–Meier plots for overall survival for primary tumors stratified for (a) >10% and <10% phospho-ERK-positive tumor cells, as analyzed with the antibody (Ab) 20G11, (b) >10% and <10% phospho-ERK-positive tumor cells, as analyzed with the Ab E10, and (c) the intensity of RKIP staining. Overall survival was measured from diagnosis of primary vertical growth-phase melanoma to time of death. In panels a, b, and c, the data from 46, 94, and 92 patients, respectively, were included. Journal of Investigative Dermatology 2008 128, 2003-2012DOI: (10.1038/jid.2008.30) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions