Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia.
Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia.
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DOI：
10.1002/j.1460-2075.1996.tb00384.x
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发表时间：
1996-02
期刊：
影响因子：
--
通讯作者：
M. K. Webster;D. Donoghue
中科院分区：
文献类型：
--
作者：
M. K. Webster;D. Donoghue
软骨发育不全是侏儒症最常见的遗传形式，是一种常染色体显性遗传疾病，其潜在机制是长骨软骨生长板成熟缺陷。软骨发育不全最近已被证明是由成纤维细胞生长因子受体3（FGFR3）的跨膜结构域中的Gly至Arg取代引起的，尽管这种突变的分子后果尚未被研究。通过用野生型和突变型FGFR 3的跨膜结构域取代Neu受体酪氨酸激酶的跨膜结构域，显示FGFR 3中的Arg380突变激活该嵌合受体的激酶和转化活性。具有能够参与氢键形成的侧链的残基，包括Glu、Asp，以及在较小程度上的Gln、His和Lys，能够取代激活的Arg380突变。Arg380点突变还引起FGFR 3本身的酪氨酸激酶活性的配体非依赖性刺激，以及受体上磷酸酪氨酸的组成性水平的极大增加。这些结果表明，软骨发育不全的分子基础是通过FGFR3的不受调节的信号转导，这可能导致不适当的软骨生长板分化，从而导致异常的长骨发育。软骨发育不全可能是FGFR家族成员的组成性激活导致发育异常的先天性疾病之一。
Achondroplasia, the most common genetic form of dwarfism, is an autosomal dominant disorder whose underlying mechanism is a defect in the maturation of the cartilage growth plate of long bones. Achondroplasia has recently been shown to result from a Gly to Arg substitution in the transmembrane domain of the fibroblast growth factor receptor 3 (FGFR3), although the molecular consequences of this mutation have not been investigated. By substituting the transmembrane domain of the Neu receptor tyrosine kinase with the transmembrane domains of wild‐type and mutant FGFR3, the Arg380 mutation in FGFR3 is shown to activate both the kinase and transforming activities of this chimeric receptor. Residues with side chains capable of participating in hydrogen bond formation, including Glu, Asp, and to a lesser extent, Gln, His and Lys, were able to substitute for the activating Arg380 mutation. The Arg380 point mutation also causes ligand‐independent stimulation of the tyrosine kinase activity of FGFR3 itself, and greatly increased constitutive levels of phosphotyrosine on the receptor. These results suggest that the molecular basis of achondroplasia is unregulated signal transduction through FGFR3, which may result in inappropriate cartilage growth plate differentiation and thus abnormal long bone development. Achondroplasia may be one of the number of cogenital disorders where constitutive activation of a member of the FGFR family leads to development abnormalities.