BRAF and MEK mutations make a late entrance.
The small guanosine triphosphatase KRAS and the protein kinases BRAF, which is a mitogen-activated protein kinase kinase kinase (MAPKKK), and mitogen-activated protein kinase kinase 1 and 2 (MAPKK1/2, also known as MKK1/2 or MEK1/2) are signaling partners in the MAPK signal transduction pathway. They are involved in many biological processes and play crucial roles during embryonic development. When inappropriately expressed, KRAS, BRAF, and MEK1/2 are also frequently implicated in tumor progression. Hence, it might reasonably have been predicted that either loss- or gain-of-function germline mutations in the genes that encode them would cause embryonic death. However, in a surprising development, two articles report that germline mutations in the KRAS, BRAF, and MEK1/2 genes are associated with cardio-facio-cutaneous (CFC) syndrome. This unexpected discovery demonstrates that mutations in KRAS, BRAF, and MEK can pass through the germline to cause specific developmental syndromes. This finding will undoubtedly stimulate further research into the function of these proteins in development and in both inherited and sporadic cancers.
Van Andel Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA. nick.duesbery@vai.org
Nick
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Duesbery
George
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Vande Woude
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D047108:Embryonic Development; D005145:Face / Q000002:abnormalities; D011905:Genes, ras; D018095:Germ-Line Mutation; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D048370:MAP Kinase Kinase 2 / Q000235:genetics; D020935:MAP Kinase Signaling System; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012868:Skin Abnormalities / Q000235:genetics; D013577:Syndrome
C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases