Human Molecular Genetics Advance Access published online on November 2, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm319
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Germline mutations of MEK in cardio-facio-cutaneous (CFC) syndrome are sensitive to MEK and RAF inhibition: Implications for therapeutic options
1 Department of Pathology, School of Medicine, University of California, San Francisco, San Francisco, California 94143-0128, USA 2 UCSF Comprehensive Cancer Center and Cancer Research Institute, University of California, San Francisco, San Francisco, California 94143-0128, USA 3 Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, JAPAN 4 Department of Pediatrics, School of Medicine, University of California, San Francisco, San Francisco, California 94143-0128, USA
* To whom correspondence should be addressed: Postal Mail: 2340 Sutter Street N111, UCSF Mt. Zion Cancer Research Building, San Francisco, California 94143-0128, USA. Phone: +1-415-514-0870 Fax: +1-415-502-3179 E-mail: tetsu{at}cc.ucsf.edu
Received September 9, 2007; Revised October 29, 2007; Accepted October 29, 2007
Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmental disorder characterized by distinctive craniofacial features, heart defects, mental retardation, and ectodermal abnormalities. We recently reported missense germline mutations in the genes MEK1 and MEK2 in patients with CFC. These mutations, including F53S and Y130C MEK1, and F57C MEK2, are the first naturally occurring mutations to be identified in these genes. This study reports data concerning the biochemical functions of the novel mutants, as well as the roles of these MEK genes in the MAPK signaling cascade. Our CFC MEK variants cannot induce ERK unless they are phosphorylated by RAF at two key serine residues in the regulatory loop. When we replaced the serine residues with alanines, ERK phosphorylation was significantly reduced in the presence of RAF. We did find that F57C MEK2 activation was less dependent on RAF signaling than the other mutants. This difference results in F57C MEK2 being resistant to the selective RAF inhibitor SB-590885. All three mutants are sensitive to the MEK inhibitor U0126. The majority of CFC cases result from mutations in B-RAF. A recent report indicates the possibility that cancer cells with activated B-RAF have enhanced, selective sensitivity to MEK inhibitors. Thus, regardless of mutations identified in an individual with CFC, MEK inhibition is a potential therapeutic approach for this population.
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