c-Src trafficking and co-localization with the EGF receptor promotes EGF ligand-independent EGF receptor activation and signaling
c-Src trafficking and co-localization with the EGF receptor promotes EGF ligand-independent EGF receptor activation and signaling
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DOI：
10.1016/j.cellsig.2008.03.007
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发表时间：
2008-07-01
影响因子：
4.8
通讯作者：
Resh, Marilyn D.
中科院分区：
文献类型：
--
作者：
Donepudi, Mrudula;Resh, Marilyn D.
c-Src 是一种非受体酪氨酸激酶，与质膜和内体区室相关。在许多人类癌症中，尤其是乳腺癌中，c-Src 和 EGF 受体 (EGFR) 过度表达。 c-Src 和 EGFR 的双重过表达与 Src 依赖性的 EGFR 激活增加相关，并且这两种酪氨酸激酶之间的协同作用增加了 EGFR 的有丝分裂活性。尽管对 c-Src 和 EGFR 之间的功能相互作用进行了广泛的研究，但人们对这两种蛋白质运输途径中的相互作用及其如何影响信号传导知之甚少。鉴于c-Src和EGFR之间的协同作用，以及EGFR被内化并且可以从内体发出信号的发现，我们假设c-Src和EGFR通过内吞途径一起运输。在这里，我们使用可调节的 c-SrcGFP 融合蛋白，它是 c-Src 的真正市场，以表明 c-Src 经历从质膜到内吞区室的组成型巨胞饮作用。 c-Src 的运动取决于其酪氨酸激酶活性。用 EGF 刺激细胞表明，c-Src 进入具有激活 EGFR 的细胞，并且 c-Src 表达和激酶活性延长了 EGFR 激活。令人惊讶的是，即使不添加 EGF，c-Src 表达也会诱导 EGFR 和 EGFR 介导的下游信号传导靶标 ERK 和 Shc 的激活。这些数据表明，当这两种激酶一起运输时，c-Src 和 EGFR 之间也会发生协同作用，并且它们的共定位促进 EGFR 介导的信号传导。 (c) 2008 Elsevier Inc. 保留所有权利。
c-Src is a non-receptor tyrosine kinase that associates with both the plasma membrane and endosomal compartments. In many human cancers, especially breast cancer, c-Src and the EGF receptor (EGFR) are overexpressed. Dual overexpression of c-Src and EGFR correlates with a Src-dependent increase in activation of EGFR, and synergism between these two tyrosine kinases increases the mitogenic activity of EGFR. Despite extensive studies of the functional interaction between c-Src and EGFR, little is known about the interactions in the trafficking pathways for the two proteins and how that influences signaling. Given the synergism between c-Src and EGFR, and the finding that EGFR is internalized and can signal from endosomes, we hypothesized that c-Src and EGFR traffic together through the endocytic pathway. Here we use a regulatable c-SrcGFP fusion protein that is a bona fide market for c-Src to show that c-Src undergoes constitutive macropinocytosis from the plasma membrane into endocytic compartments. The movement of c-Src was dependent on its tyrosine kinase activity. Stimulation of cells with EGF revealed that c-Src traffics into the cell with activated EGFR and that c-Src expression and kinase activity prolongs EGFR activation. Surprisingly, even in the absence of EGF addition, c-Src expression induced activation of EGFR and of EGFR-mediated downstream signaling targets ERK and Shc. These data suggest that the synergy between c-Src and EGFR also occurs as these two kinases traffic together, and that their co-localization promotes EGFR-mediated signaling. (c) 2008 Elsevier Inc. All rights reserved.