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c-Src trafficking and co-localization with the EGF Receptor promotes EGF ligand-independent EGF Receptor Activation and Signaling

机译：c-Src转运和与EGF受体的共定位促进EGF配体独立的EGF受体激活和信号传导

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摘要

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 marker 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 colocalization promotes EGFR-mediated signaling.
机译：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，尤其是乳腺癌中，c-Src和EGF受体（EGFR）过度表达。 c-Src和EGFR的双重过度表达与EGFR激活中Src依赖性增加有关，并且这两个酪氨酸激酶之间的协同作用增加了EGFR的促有丝分裂活性。尽管对c-Src和EGFR之间的功能相互作用进行了广泛的研究，但对于这两种蛋白质的运输途径中的相互作用以及其如何影响信号传导的了解甚少。考虑到c-Src和EGFR之间的协同作用，以及发现EGFR被内在化并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，我们使用一种可调节的c-SrcGFP融合蛋白，它是c-Src的真正标志，以显示c-Src从质膜进入内吞性区室进行组成型巨胞吞。 c-Src的运动取决于其酪氨酸激酶活性。用EGF刺激细胞后，发现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的激活。令人惊讶地，即使在不添加EGF的情况下，c-Src表达也诱导EGFR和EGFR介导的下游信号传导靶标ERK和Shc的活化。这些数据表明，当这两种激酶一起运输时，c-Src和EGFR之间也发生协同作用，并且它们的共定位促进EGFR介导的信号传导。

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    Mrudula Donepudi; Marilyn D. Resh;

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  • 年(卷),期 -1(20),7
  • 年度 -1
  • 页码 1359–1367
  • 总页数 18
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