title: Regulation of ERK3/MAPK6 expression by BRAF.
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.
authors.affiliation: Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Michael T
authors.initials: MT
authors.lastname: Eby
authors.forename: William F
authors.initials: WF
authors.lastname: Forrest
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Gray
authors.forename: Janet Y
authors.initials: JY
authors.lastname: Tien
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Murray
authors.forename: David P
authors.initials: DP
authors.lastname: Davis
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
mesh_terms: D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D048053:Mitogen-Activated Protein Kinase 6 / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048053:Mitogen-Activated Protein Kinase 6