Folliculin Interacts with Rab35 to Regulate EGF-Induced EGFR Degradation.
Folliculin Interacts with Rab35 to Regulate EGF-Induced EGFR Degradation.
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毛囊素与 Rab35 相互作用调节 EGF 诱导的 EGFR 降解
DOI：
10.3389/fphar.2017.00688
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发表时间：
2017
影响因子：
5.6
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Zheng J;Duan B;Sun S;Cui J;Du J;Zhang Y
目的和假设：本研究旨在探讨EGF诱导EGFR降解的细胞内调控机制。方法：采用蛋白质印迹法检测EGFR信号通路相关蛋白的磷酸化。分别用pulldown、免疫共沉淀法检测Rab 35的激活、Rab 35与滤泡素（FLCN）的连接。采用基因过表达和敲低技术检测FLCN与细胞生长的关系。结果如下：在这里，我们证明，干扰FLCN，一种肿瘤抑制因子，降低EGF诱导的EGFR降解率，导致下游信号的激活延长。Rab 35也参与了这些过程。此外，FLCN的C-末端结合并激活Rab 35。特别令人感兴趣的是观察到厄洛替尼，一种选择性EGFR抑制剂，不仅阻碍EGFR介导的细胞信号传导，而且消除EGF刺激的EGFR降解。进一步的结果表明，EGF促进Rab 35的活化，FLCN调节EGF依赖的Rab 35活化和细胞生长。结论：总之，我们的研究提出了一个负反馈调节模型，其中FLCN介导EGF诱导的Rab 35激活，从而增加EGFR降解和减弱EGFR信号传导。
Aims and Hypothesis: This study aims to investigate the mechanism involved in intracellular regulation of EGFR degradation induced by EGF. Methods: Phosphorylation of proteins related to EGFR signaling was examined by western blot analysis. Activation, connection between Rab35 and folliculin (FLCN) were assessed by pulldown, coimmunoprecipitation assays separately. The relationship between FLCN and cell growth was detected using gene overexpression and knock-down techniques. Results: Here, we demonstrate that interfering with FLCN, a tumor suppressor, reduces the rate of EGF-induced EGFR degradation, resulting in prolonged activation of downstream signaling. Rab35 is also involved in these processes. Moreover, C-terminal of FLCN binds to and activates Rab35. Of special interest is the observation that erlotinib, a selective EGFR inhibitor, not only obstructs the EGFR-mediated cellular signaling, but also abolishes EGF-stimulated EGFR degradation. Further results reveal that EGF facilitates the activation of Rab35, and FLCN modulates EGF-dependent Rab35 activation and cell growth. Conclusions: Taken together, our study proposes a negative-feedback regulation model in which FLCN mediates EGF-induced Rab35 activation, thereby increasing EGFR degradation and attenuating EGFR signaling.