c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF
c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF
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DOI：
10.1101/gad.13.18.2400
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发表时间：
1999-09-15
影响因子：
10.5
通讯作者：
Pendergast, AM
中科院分区：
文献类型：
--
作者：
Plattner, R;Kadlec, L;Pendergast, AM
c-Abl酪氨酸激酶除了定位于细胞核之外还定位于细胞质和质膜。然而，很少有关于c-Abl在细胞质/质膜隔室中的作用的信息。在这里，我们报告的c-Abl的膜池被激活的生长因子PDGF和EGF在成纤维细胞。活化的模式和动力学类似于Src家族激酶的生长因子活化。为了确定c-Abl的激活和Src家族成员之间是否存在联系，我们检测了表达致癌Src蛋白的细胞中c-Abl激酶的活性。我们发现c-Abl激酶活性在这些细胞中增加了10- 20倍，并且Src和Fyn激酶在体外直接磷酸化c-Abl。此外，野生型Src的过度表达增强了生长因子对c-Abl的激活，而Src的激酶失活形式降低了这种激活，表明生长因子对Abl的激活至少部分是通过Src激酶的激活而发生的。值得注意的是，我们发现c-Abl在对PDGF的形态学反应中具有功能性作用。而PDGF处理血清饥饿的野生型小鼠胚胎成纤维细胞导致明显的线性或环形/背膜皱褶，c-Abl-null细胞表现出对PDGF应答的皱褶显著减少，其通过c-Abl的生理再表达而被拯救。这些数据鉴定c-Abl作为活化受体酪氨酸激酶和Src家族激酶的下游靶，并首次表明c-Abl在细胞对生长因子的反应中起作用。
The c-Abl tyrosine kinase localizes to the cytoplasm and plasma membrane in addition to the nucleus. However, there is little information regarding a role for c-Abl in the cytoplasm/plasma membrane compartments. Here we report that a membrane pool of c-Abl is activated by the growth factors PDGF and EGF in fibroblasts. The pattern and kinetics of activation are similar to growth factor activation of Src family kinases. To determine whether a link existed between activation of c-Abl and members of the Src family, we examined c-Abl kinase activity in cells that expressed oncogenic Src proteins. We found that c-Abl kinase activity was increased by 10- to 20-fold in these cells, and that Src and Fyn kinases directly phosphorylated c-Abl in vitro. Furthermore, overexpression of wild-type Src potentiated c-Abl activation by growth factors, and a kinase-inactive form of Src reduced this activation, showing that Abl activation by growth factors occurs at least in part via activation of Src kinases. Significantly, we show that c-Abl has a functional role in the morphological response to PDGF. Whereas PDGF treatment of serum-starved wild-type mouse embryo fibroblasts resulted in distinct linear or circular/dorsal membrane ruffling, c-Abl-null cells demonstrated dramatically reduced ruffling in response to PDGF, which was rescued by physiological re-expression of c-Abl. These data identify c-Abl as a downstream target of activated receptor tyrosine kinases and Src family kinases, and show for the first time that c-Abl functions in the cellular response to growth factors.