RILP suppresses invasion of breast cancer cells by modulating the activity of RalA through interaction with RalGDS.
RILP suppresses invasion of breast cancer cells by modulating the activity of RalA through interaction with RalGDS.
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RILP 通过与 RalGDS 相互作用调节 RalA 的活性来抑制乳腺癌细胞的侵袭。
DOI：
10.1038/cddis.2015.266
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发表时间：
2015-10-15
影响因子：
9
通讯作者：
Wang T
中科院分区：
文献类型：
--
作者：
Wang Z;Zhou Y;Hu X;Chen W;Lin X;Sun L;Xu X;Hong W;Wang T
RILP（Rab7 相互作用溶酶体蛋白）是晚期内体/溶酶体运输的关键调节因子，并且可能是前列腺癌的肿瘤抑制因子。然而，RILP在其他癌症中的作用以及RILP调节癌细胞侵袭的潜在机制仍有待研究。在这项研究中，我们发现乳腺癌细胞中 RILP 的过度表达会抑制迁移和侵袭，而 RNAi 介导的敲低导致的 RILP 耗竭会促进迁移和侵袭。我们将 RalGDS（Ral 鸟嘌呤核苷酸解离刺激剂）确定为 RILP 的新型相互作用伙伴，截断分析表明 RILP 的 N 末端区域负责与 RalGDS 的鸟嘌呤核苷酸交换因子 (GEF) 结构域相互作用。免疫荧光显微镜显示 RalGDS 可以通过 RILP 募集到晚期内体区室。进一步的研究表明，RILP 的过表达会抑制 RalGDS 下游靶标 RalA 的活性。我们的数据表明，RILP 通过与 RalGDS 相互作用，抑制其 GEF 对 RalA 的活性，从而抑制乳腺癌细胞的侵袭。
RILP (Rab7-interacting lysosomal protein) is a key regulator for late endosomal/lysosomal trafficking, and probably a tumor suppressor in prostate cancer. However, the role of RILP in other cancers and the underlying mechanism for RILP in regulating the invasion of cancer cells remain to be investigated. In this study, we showed that overexpression of RILP in breast cancer cells inhibits the migration and invasion, whereas the depletion of RILP by RNAi-mediated knockdown promotes the migration and invasion. We identified RalGDS (Ral guanine nucleotide dissociation stimulator) as a novel interacting partner for RILP, and truncation analysis revealed the N-terminal region of RILP is responsible for interacting with the guanine nucleotide exchange factor (GEF) domain of RalGDS. Immunofluorescence microscopy revealed that RalGDS can be recruited to the late endosomal compartments by RILP. Further investigations indicated that the overexpression of RILP inhibits the activity of RalA, a downstream target of RalGDS. Our data suggest that RILP suppresses the invasion of breast cancer cells by interacting with RalGDS to inhibit its GEF activity for RalA.