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首页> 外文期刊>Molecular and Cellular Biology >Increased BRAF Heterodimerization Is the Common Pathogenic Mechanism for Noonan Syndrome-Associated RAF1 Mutants
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Increased BRAF Heterodimerization Is the Common Pathogenic Mechanism for Noonan Syndrome-Associated RAF1 Mutants

机译：增加的BRAF异二聚化是Noonan综合征相关RAF1突变体的常见致病机制。

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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 Raf1D486N. Raf1D486N/+ (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 Raf1D486N-expressing cells compared with controls. RAF1D486N, 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.
机译：Noonan综合征（NS）是一种相对常见的常染色体显性遗传疾病，其特征是先天性心脏缺陷，身材矮小和面部畸形。 NS是由RAS–RAF–MEK–细胞外信号调节激酶（ERK）丝裂原激活的蛋白激酶（MAPK）途径的多个组成部分中的种系突变引起的，包括的激酶激活和激酶受损等位基因RAF1 （约3至5％），它编码MEK1 / 2的丝氨酸-苏氨酸激酶。为了研究激酶受损的RAF1突变体如何引起NS，我们产生了表达 Raf1 D486N 的敲入小鼠。 Raf1 D486N / + （在此为D486N / +）雌性小鼠表现出轻度的生长缺陷。雄性和雌性D486N / D486N小鼠发展为同心心脏肥大，但不完全穿透，但存在严重的生长缺陷。值得注意的是，与对照相比，表达Raf1 D486N 的细胞中Mek / Erk的活化作用增强。 RAF1 D486N 以及其他激酶受损的RAF1突变体显示出与BRAF的异源二聚化增加，这对于促进增加的MEK / ERK活化是必要且充分的。此外，激酶激活的 RAF1 突变体还需要异二聚化以增强MEK / ERK激活。我们的结果表明，增加的异二聚能力是NS相关的 RAF1 突变的常见致病机制。

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