| First Author | Wu X | Year | 2012 |
| Journal | Mol Cell Biol | Volume | 32 |
| Issue | 19 | Pages | 3872-90 |
| PubMed ID | 22826437 | Mgi Jnum | J:189143 |
| Mgi Id | MGI:5444541 | Doi | 10.1128/MCB.00751-12 |
| Citation | Wu X, et al. (2012) Increased BRAF heterodimerization is the common pathogenic mechanism for noonan syndrome-associated RAF1 mutants. Mol Cell Biol 32(19):3872-90 |
| abstractText | 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 ( approximately 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. |
