title: Increased BRAF heterodimerization is the common pathogenic mechanism for noonan syndrome-associated RAF1 mutants.
abstract: Noonan syndrome (NS) is a relatively common autosomal dominant disorder characterized by congenital heart defects, short stature, and facial dysmorphia. NS is caused by germ line mutations in several components of the RAS-RAF-MEK-extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway, including both kinase-activating and kinase-impaired alleles of RAF1 (∼3 to 5%), which encodes a serine-threonine kinase for MEK1/2. To investigate how kinase-impaired RAF1 mutants cause NS, we generated knock-in mice expressing Raf1(D486N). Raf1(D486N/+) (here D486N/+) female mice exhibited a mild growth defect. Male and female D486N/D486N mice developed concentric cardiac hypertrophy and incompletely penetrant, but severe, growth defects. Remarkably, Mek/Erk activation was enhanced in Raf1(D486N)-expressing cells compared with controls. RAF1(D486N), as well as other kinase-impaired RAF1 mutants, showed increased heterodimerization with BRAF, which was necessary and sufficient to promote increased MEK/ERK activation. Furthermore, kinase-activating RAF1 mutants also required heterodimerization to enhance MEK/ERK activation. Our results suggest that an increased heterodimerization ability is the common pathogenic mechanism for NS-associated RAF1 mutations.
authors: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: Xue
authors: X
authors: Wu
authors: Jiani
authors: J
authors: Yin
authors: Jeremy
authors: J
authors: Simpson
authors: Kyoung-Han
authors: KH
authors: Kim
authors: Shengqing
authors: S
authors: Gu
authors: Jenny H
authors: JH
authors: Hong
authors: Peter
authors: P
authors: Bayliss
authors: Peter H
authors: PH
authors: Backx
authors: Benjamin G
authors: BG
authors: Neel
authors: Toshiyuki
authors: T
authors: Araki
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009634:Noonan Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017354:Point Mutation; D055503:Protein Multimerization; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics* / Q000378:metabolism
chemical_list: D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf