ROR1-CAVIN3 interaction required for caveolae-dependent endocytosis and pro-survival signaling in lung adenocarcinoma
ROR1-CAVIN3 interaction required for caveolae-dependent endocytosis and pro-survival signaling in lung adenocarcinoma
复制标题
肺腺癌中小窝依赖性内吞作用和促生存信号传导所需的 ROR1-CAVIN3 相互作用
DOI：
10.1038/s41388-019-0785-7
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发表时间：
2019
期刊：
影响因子：
8
通讯作者：
Takahashi T.
中科院分区：
文献类型：
--
作者：
Yamaguchi T;Hayashi M;Ida L;Yamamoto M;Lu C;Kajino T;Cheng J;Nakatochi M;Isomura H;Yamazaki M;Suzuki M;Fujimoto T;Takahashi T.
受体酪氨酸激酶样孤儿受体1（ROR 1）是肺腺癌中谱系存活癌基因NKX 2 -1/TTF-1的转录靶点。除了其激酶依赖性作用之外，ROR 1还充当支架蛋白以促进小窝蛋白-1（CAV 1）和CAVIN 1之间的相互作用，并因此维持小窝形成，其进而维持来自多种受体酪氨酸激酶（RTK）的朝向AKT的促存活信号传导，所述多种受体酪氨酸激酶包括表皮生长因子受体（EGFR）、MET（原癌基因，受体酪氨酸激酶）和IGF-IR（胰岛素样生长因子受体1）。因此，ROR 1是克服EGFR-TKI耐药性的有吸引力的靶标，这是由于各种机制，如EGFR T790 M双突变和来自其他RTK的旁路信号传导。在这里，我们报告说，ROR 1具有一个新的支架功能，有效的小窝依赖性内吞作用不可或缺。发现CAVIN 3与ROR 1结合的位点与CAV 1和CAVIN 1的位点不同，这是正确的CAVIN 3亚细胞定位和小窝依赖性内吞作用所需的一种新功能，但不是小窝形成本身。此外，还获得了ROR 1-CAVIN 3相互作用和随后的小窝运输之间的机制联系的证据，发现其利用与ROR 1与CAV 1和CAVIN 1相互作用不同的结合位点，其中RTK介导的促存活信号传导朝向肺腺癌细胞中早期内体中的AKT。目前的研究结果保证了未来的研究，以开发新的治疗策略来抑制ROR 1的多方面支架功能，以减少这种毁灭性癌症造成的无法忍受的死亡人数。
The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transcriptional target of the lineage-survival oncogene NKX2–1/TTF-1 in lung adenocarcinomas. In addition to its kinase-dependent role, ROR1 functions as a scaffold protein to facilitate interaction between caveolin-1 (CAV1) and CAVIN1, and consequently maintains caveolae formation, which in turn sustains pro-survival signaling toward AKT from multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET (proto-oncogene, receptor tyrosine kinase), and IGF-IR (insulin-like growth factor receptor 1). Therefore, ROR1 is an attractive target for overcoming EGFR-TKI resistance due to various mechanisms such as EGFR T790M double mutation and bypass signaling from other RTKs. Here, we report that ROR1 possesses a novel scaffold function indispensable for efficient caveolae-dependent endocytosis. CAVIN3 was found to bind with ROR1 at a site distinct from sites for CAV1 and CAVIN1, a novel function required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis, but not caveolae formation itself. Furthermore, evidence of a mechanistic link between ROR1-CAVIN3 interaction and consequential caveolae trafficking, which was found to utilize a binding site distinct from those for ROR1 interactions with CAV1 and CAVIN1, with RTK-mediated pro-survival signaling towards AKT in early endosomes in lung adenocarcinoma cells was also obtained. The present findings warrant future study to enable development of novel therapeutic strategies for inhibiting the multifaceted scaffold functions of ROR1 in order to reduce the intolerable death toll from this devastating cancer.