CELL-TRANSFORMATION BY FIBROBLAST GROWTH-FACTORS CAN BE SUPPRESSED BY TRUNCATED FIBROBLAST GROWTH-FACTOR RECEPTORS
CELL-TRANSFORMATION BY FIBROBLAST GROWTH-FACTORS CAN BE SUPPRESSED BY TRUNCATED FIBROBLAST GROWTH-FACTOR RECEPTORS
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DOI：
10.1128/mcb.14.11.7660
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发表时间：
1994-11-01
影响因子：
5.3
通讯作者：
MANSUKHANI, A
中科院分区：
文献类型：
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作者：
LI, Y;BASILICO, C;MANSUKHANI, A
配体诱导的二聚化和转磷酸化被认为是受体酪氨酸激酶产生细胞信号的重要事件。我们研究了信号传导缺陷型、截短的成纤维细胞生长因子 (FGF) 受体（FGFR-1 和 FGFR-2）阻断表达两种类型内源性 FGF 受体的细胞中 FGF 反应的能力。当这些显性失活受体在被分泌的 FGF-4 转化的 NIH 3T3 细胞中表达时，细胞的转化特性可以不同程度地恢复，更好的恢复表型与更高水平的截短受体表达相关。此外，截短的 FGFR-2 在产生回复方面比 FGFR-1 显着更有效，表明 FGF-4 优先利用 FGFR-2 信号传导途径。表达这些截短受体的 NIH 3T3 克隆对 FGF 诱导的有丝分裂更具抵抗力，并且在用 FGF 处理后还表现出酪氨酸磷酸化降低。然而，FGF 信号传导的阻断可以通过添加过量的生长因子来克服。根据斯卡查德分析测量，截短受体的结合亲和力比野生型受体低四到八倍。我们还观察到截短受体表达克隆对 FGF-2 或 FGF-4 的反应具有部分特异性。我们的结果表明，对激酶阴性 FGF 受体产生的信号转导的阻断是通过显性负效应和生长因子与功能受体结合的竞争的组合来实现的。
Ligand-induced dimerization and transphosphorylation are thought to be important events by which receptor tyrosine kinases generate cellular signals. We have investigated the ability of signalling-defective, truncated fibroblast growth factor (FGF) receptors (FGFR-1 and FGFR-2) to block the FGF response in cells that express both types of endogenous FGF receptors. When these dominant negative receptors are expressed in NIH 3T3 cells transformed by the secreted FGF-4 the transformed properties of the cells can be reverted to various degrees, with better reversion phenotype correlating with higher levels of truncated receptor expression. Furthermore, truncated FGFR-2 is significantly more efficient at producing reversion than FGFR-1, indicating that FGF-4 preferentially utilizes the FGFR-2 signalling pathway. NIH 3T3 clones expressing these truncated receptors are more resistant to FGF-induced mitogenesis and also exhibit reduced tyrosine phosphorylation upon treatment with FGF. The block in FGF-signalling, however, can be overcome by the addition of excess growth factor. The truncated receptors have binding affinities that are four- to eightfold lower than those of wild-type receptors, as measured by Scatchard analysis. We also observed a partial specificity in the responses of truncated-receptor-expressing clones to FGF-2 or FGF-4. Our results suggest that the block to signal transduction produced by kinase-negative FGF receptors is achieved through a combination of dominant negative effects and competition for growth factor binding with functional receptors.