Abstract |
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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Authors | Thanaset Senawong, Janyaporn Phuchareon, Osamu Ohara, Frank McCormick, Katherine A Rauen, Osamu Tetsu |
Journal | Human molecular genetics
(Hum Mol Genet)
Vol. 17
Issue 3
Pg. 419-30
(Feb 01 2008)
ISSN: 1460-2083 [Electronic] England |
PMID | 17981815
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Imidazoles
- Protein Kinase Inhibitors
- Recombinant Proteins
- SB-590885
- MAP2K2 protein, human
- raf Kinases
- MAP Kinase Kinase 1
- MAP Kinase Kinase 2
- MAP2K1 protein, human
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Topics |
- Animals
- Binding Sites
(genetics)
- COS Cells
- Cell Line
- Chlorocebus aethiops
- Craniofacial Abnormalities
(drug therapy, genetics, metabolism)
- Germ-Line Mutation
- Heart Defects, Congenital
(drug therapy, genetics, metabolism)
- Humans
- Imidazoles
(pharmacology)
- MAP Kinase Kinase 1
(antagonists & inhibitors, genetics, metabolism)
- MAP Kinase Kinase 2
(genetics, metabolism)
- MAP Kinase Signaling System
(drug effects, genetics)
- Phosphorylation
- Protein Kinase Inhibitors
(pharmacology)
- Rats
- Recombinant Proteins
(genetics, metabolism)
- Skin Abnormalities
(drug therapy, genetics, metabolism)
- Syndrome
- raf Kinases
(antagonists & inhibitors)
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