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Increased BRAF heterodimerization is the common pathogenic mechanism for noonan syndrome-associated RAF1 mutants.

Authors: Wu, Xue  Yin, Jiani  Simpson, Jeremy  Kim, Kyoung-Han  Gu, Shengqing  Hong, Jenny H  Bayliss, Peter  Backx, Peter H  Neel, Benjamin G  Araki, Toshiyuki 
Citation: Wu X, etal., Mol Cell Biol. 2012 Oct;32(19):3872-90. doi: 10.1128/MCB.00751-12. Epub 2012 Jul 23.
Pubmed: (View Article at PubMed) PMID:22826437
DOI: Full-text: DOI:10.1128/MCB.00751-12

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.

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CRRD Object Information
CRRD ID: 12910709
Created: 2017-06-21
Species: All species
Last Modified: 2017-06-21
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.