Regulation of ERK3/MAPK6 expression by BRAF

  • Authors: Klaus P. Hoeflich, Michael T. Eby, William F. Forrest, Daniel C. Gray, Janet Y. Tien, Howard M. Stern, Lesley J. Murray, David P. Davis, Zora Modrusan, Somasekar Seshagiri
  • View Affiliations

  • Published online on: Sunday, October 1, 2006
  • Pages: 839-849
  • DOI: 10.3892/ijo.29.4.839

Abstract

Several forms of cancer are characterized by frequent activating mutations in the serine/threonine kinase, BRAF. Substitution of glutamic acid for valine at codon 600 (V600E) accounts for approximately 90% of all BRAF activating mutations and leads to stimulation of kinase activity, downstream signaling, and cell transformation. To better understand the molecular pathogenesis induced by oncogenic BRAF signaling, we used microarray gene expression profiling to comprehensively analyze the BRAF-directed transcriptional program of cells expressing a conditionally active form of BRAFV600E. Several novel genes that affect proliferation, cell survival, angiogenesis and immune surveillance were identified as possible mediators of BRAF-induced oncogenic signaling. Moreover, we show that a MAPK family member, extracellular signal-regulated kinase-3 (ERK3/MAPK6) is highly expressed in response to BRAF signaling in this system. Cellular ERK3 protein is highly unstable and pharmacological inhibition of BRAF activity resulted in rapid ERK3 degradation. In melanoma cells, RNAi-mediated knockdown of endogenous BRAF or treatment with MEK inhibitors that prevent ERK1/2 activation led to a reduction in ERK3 levels, indicating that elevated ERK3 expression is mediated through MEK1/2 signaling. These results provide strong evidence for another mode by which BRAF can regulate the ERK protein kinase family and suggest ERK3 to be a potential pharmacodynamic marker for targeting BRAF signaling in melanoma.
Journal Cover

October 2006
Volume 29 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

2013 Impact Factor: 2.773
Ranked #30/202 Oncology
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APA
Hoeflich, K., Eby, M., Forrest, W., Gray, D., Tien, J., Stern, H., Murray, L., Davis, D., Modrusan, Z., & Seshagiri, S. (2006). Regulation of ERK3/MAPK6 expression by BRAF. International Journal of Oncology, 29(4), 839-849.
MLA
Hoeflich, Eby, Forrest, Gray, Tien, Stern, Murray, Davis, Modrusan, and Somasekar Seshagiri. "Regulation of ERK3/MAPK6 expression by BRAF." International Journal of Oncology International Journal of Oncology 29.4 (2006): 839-849.
Chicago
Hoeflich, Eby, Forrest, Gray, Tien, Stern, Murray, Davis, Modrusan, and Somasekar Seshagiri. "Regulation of ERK3/MAPK6 expression by BRAF." International Journal of Oncology International Journal of Oncology 29 no. 4 (2006): 839-849.