Distinct Involvement of the Gab1 and Grb2 Adaptor Proteins in Signal Transduction by the Related Receptor Tyrosine Kinases RON and MET
Distinct Involvement of the Gab1 and Grb2 Adaptor Proteins in Signal Transduction by the Related Receptor Tyrosine Kinases RON and MET
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DOI：
10.1074/jbc.m111.239384
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发表时间：
2011-09-16
影响因子：
4.8
通讯作者：
Ashkenazi, Avi
中科院分区：
文献类型：
--
作者：
Chaudhuri, Amitabha;Xie, Ming-Hong;Ashkenazi, Avi
尽管受体酪氨酸激酶 MET 的信号转导机制已明确，但对其密切相关的 RON 知之甚少。 MET 通过特定细胞质酪氨酸的自磷酸化启动细胞内信号传导，这些酪氨酸形成接头蛋白 Grb2 和 Gab1 的对接位点。 Grb2 直接结合，并且对于 MET 的所有生物活性至关重要。 Gab1 直接或间接通过 Grb2 对接，仅控制 MET 功能的子集。由于 MET 和 RON 具有相似的接头结合位点，因此预计它们的接头相互作用将是保守的。在这里我们表明，与 MET 相比，RON 主要依赖 Gab1 进行信号传输。令人惊讶的是，破坏 RON 的 Grb2 对接位点或耗尽 Grb2 会增强活性，而增强 Grb2 结合会减弱 Gab1 的募集和信号传导。因此，RON 和 MET 的适配器相互作用有所不同；此外，Grb2 在 RON 信号传导中发挥新的拮抗作用。
Although the signal transduction mechanisms of the receptor tyrosine kinase MET are well defined, less is known about its close relative RON. MET initiates intracellular signaling by autophosphorylation on specific cytoplasmic tyrosines that form docking sites for the adaptor proteins Grb2 and Gab1. Grb2 binds directly and is essential for all of the biological activities of MET. Gab1 docks either directly or indirectly via Grb2 and controls only a subset of MET functions. Because MET and RON possess similar adaptor binding sites, it was anticipated that their adaptor interactions would be conserved. Here we show that in contrast to MET, RON relies primarily on Gab1 for signal transmission. Surprisingly, disruption of the Grb2 docking site of RON or Grb2 depletion augments activity, whereas enhancement of Grb2 binding attenuates Gab1 recruitment and signaling. Hence, RON and MET differ in their adaptor interactions; furthermore, Grb2 performs a novel antagonistic role in the context of RON signaling.