Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation
Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation
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DOI：
10.1091/mbc.12.4.931
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发表时间：
2001-04-01
影响因子：
3.3
通讯作者：
Donoghue, DJ
中科院分区：
文献类型：
--
作者：
Hart, KC;Robertson, SC;Donoghue, DJ
成纤维细胞生长因子受体3 （FGFR3）突变经常与人类发育障碍和癌症有关。通过突变或配体刺激激活FGFR3，导致细胞内多个酪氨酸残基的自磷酸化。为了评估FGFR3胞内结构域内6个保守酪氨酸残基对信号传导的重要性，构建了包含质膜定位的n端肉豆蔻化信号和赋予组成型激酶激活的点突变（K650E）的衍生物。含有所有保守酪氨酸残基的衍生物刺激细胞转化和激活几种FGFR3信号通路。用苯丙氨酸取代所有非激活环酪氨酸残基使该FGFR3结构失活，尽管存在激活的K650E突变。添加单个酪氨酸残基Y724，恢复了其刺激细胞转化、磷脂酰肌醇3-激酶激活和Shp2、MAPK、Stat1和Stat3磷酸化的能力。这些结果表明，Y724在FGFR3组成型激活突变体激活多种信号通路中发挥关键作用。
Fibroblast growth factor receptor 3 (FGFR3) mutations are frequently involved in human developmental disorders and cancer. Activation of FGFR3, through mutation or ligand stimulation, results in autophosphorylation of multiple tyrosine residues within the intracellular domain. To assess the importance of the six conserved tyrosine residues within the intracellular domain of FGFR3 for signaling, derivatives were constructed containing an N-temrinal myristylation signal for plasma membrane localization and a point mutation (K650E) that confers constitutive kinase activation. A derivative containing all conserved tyrosine residues stimulates cellular transformation and activation of several FGFR3 signaling pathways. Substitution of all nonactivation loop tyrosine residues with phenylalanine rendered this FGFR3 construct inactive, despite the presence of the activating K650E mutation. Addition of a single tyrosine residue, Y724, restored its ability to stimulate cellular transformation, phosphatidylinositol 3-kinase activation, and phosphorylation of Shp2, MAPK, Stat1, and Stat3. These results demonstrate a critical role for Y724 in the activation of multiple signaling pathways by constitutively activated mutants of FGFR3.