Evolutionary divergence of platelet-derived growth factor alpha receptor signaling mechanisms
Evolutionary divergence of platelet-derived growth factor alpha receptor signaling mechanisms
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DOI：
10.1128/mcb.23.11.4013-4025.2003
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发表时间：
2003-06-01
影响因子：
5.3
通讯作者：
Soriano, P
中科院分区：
文献类型：
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作者：
Hamilton, TG;Klinghoffer, RA;Soriano, P
受体酪氨酸激酶 (RTK) 通过刺激相对少量的重叠信号通路来指导不同的细胞和发育反应。特异性可以通过 RTK 表达模式或各个信号传导途径的差异激活来确定。为了解决这个问题，我们培育了敲入小鼠，其中小鼠血小板源性生长因子α受体（PDGFαR）的胞外结构域与果蝇躯干（α（Tor））或小鼠成纤维细胞生长因子受体1（α（FR））的胞质结构域融合。 α(Tor) 纯合胚胎表现出对通常在 PDGFalphaR 缺失胚胎中常见的神经嵴和血管生成缺陷的显着挽救作用，但无法挽救骨骼或胚胎外缺陷。这种表型与 alpha(Tor) 能够刺激丝裂原激活蛋白 (MAP) 激酶通路至接近野生型水平但无法完全激活其他通路（例如磷脂酰肌醇 (PI) 3-激酶）的能力相关。 α(FR)嵌合受体无法挽救PDGFαR缺失表型的任何方面。相反，α(FR) 表达会导致异位骨发育突出的功能获得表型。 α(FR) 表型与限制 MAP 激酶信号传导和参与显着 PI3 激酶反应的失败相关。这些结果表明，不同下游信号通路的精确调节对于 RTK 功能的规范至关重要。
Receptor tyrosine kinases (RTKs) direct diverse cellular and developmental responses by stimulating a relatively small number of overlapping signaling pathways. Specificity may be determined by RTK expression patterns or by differential activation of individual signaling pathways. To address this issue we generated knock-in mice in which the extracellular domain of the mouse platelet-derived growth factor alpha receptor (PDGFalphaR) is fused to the cytosolic domain of Drosophila Torso (alpha(Tor)) or the mouse fibroblast growth factor receptor 1 (alpha(FR)). alpha(Tor) homozygous embryos exhibit significant rescue of neural crest and angiogenesis defects normally found in PDGFalphaR-null embryos yet fail to rescue skeletal or extraembryonic defects. This phenotype was associated with the ability of alpha(Tor) to stimulate the mitogen-activated protein (MAP) kinase pathway to near wildtype levels but failure to completely activate other pathways, such as phosphatidylinositol (PI) 3-kinase. The alpha(FR) chimeric receptor fails to rescue any aspect of the PDGFalphaR-null phenotype. Instead, alpha(FR) expression leads to a gain-of-function phenotype highlighted by ectopic bone development. The alpha(FR) phenotype was associated with a failure to limit MAP kinase signaling and to engage significant PI3-kinase response. These results suggest that precise regulation of divergent downstream signaling pathways is critical for specification of RTK function.