Prolonged EGFR signaling by ERBB2-mediated sequestration at the plasma membrane
Prolonged EGFR signaling by ERBB2-mediated sequestration at the plasma membrane
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DOI：
10.1111/j.1600-0854.2007.00665.x
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发表时间：
2008-01-01
期刊：
影响因子：
4.5
通讯作者：
Bastiaens, Philippe I.
中科院分区：
文献类型：
--
作者：
Offterdinger, Martin;Bastiaens, Philippe I.
我们分析了孤儿erbB2受体对表皮生长因子受体(EGFR)磷酸化的时空调节。结果表明，EGFR与erbB2的结合足以延长和增强EGFR的净磷酸化，而不依赖于erbB2的激酶活性。这种增强的EGFR信号转导机制是由erbB2介导的磷酸化的EGFR滞留在质膜(PM)，从而阻止EGFR去磷酸化和膜结合蛋白酪氨酸磷酸酶(PTPs)的信号终止所致。EGF诱导的EGFR内化确实在高水平的erbB2存在时被阻断，或者如果EGFR的CBL结合受损。这种由erbB2介导的对活化的EGFR进入笼状蛋白包裹的囊泡的阻断可以通过抗体介导的破坏EGFR和erbB2之间的相互作用而减轻。这些结果表明，erbB2介导的磷酸化EGFR在PM的优势捕获是一种延长EGFR信号的机制，通过将激活的EGFR从高PTP活性的细胞内位置隔离出来。
We have analyzed the spatial-temporal regulation of epidermal growth factor receptor (EGFR) phosphorylation by the orphan erbB2 receptor. It is shown that EGFR association with erbB2 is sufficient to prolong and enhance the net phosphorylation of EGFR, independent of the kinase activity of erbB2. This enhanced EGFR signaling was rather caused by erbB2-mediated retention of phosphorylated EGFR at the plasma membrane (PM), thereby preventing EGFR dephosphorylation and signal termination by endomembrane-bound protein tyrosine phosphatases (PTPs). EGF-induced EGFR internalization was indeed blocked in the presence of high levels of erbB2 or if cbl binding of EGFR was impaired. This erbB2-mediated blockage of the entry of activated EGFR into clathrin-coated vesicles could be alleviated by antibody-mediated disruption of the interaction between EGFR and erbB2. These results identify erbB2-mediated dominant trapping of phosphorylated EGFR at the PM as a mechanism that prolongs EGFR signaling, by sequestration of activated EGFR away from intracellular sites of high PTP activity.