Rab34 regulates adhesion, migration, and invasion of breast cancer cells
Rab34 regulates adhesion, migration, and invasion of breast cancer cells
复制标题
Rab34 调节乳腺癌细胞的粘附、迁移和侵袭
DOI：
10.1038/s41388-018-0202-7
复制
发表时间：
2018-07-05
期刊：
影响因子：
8
通讯作者：
Wang, Tuanlao
中科院分区：
文献类型：
--
作者：
Sun, Lixiang;Xu, Xiaohui;Wang, Tuanlao
小的GTP酶Rab34调节溶酶体的空间分布、分泌和巨噬细胞吞噬。在这项研究中，我们发现Rab34在侵袭性乳腺癌细胞中过表达，这意味着Rab34在乳腺癌中可能起到作用。通过shRNA沉默Rab34可抑制乳腺癌细胞的迁移、侵袭和黏附。Rab34与整合素β3的胞浆尾部特异性结合，缺失的Rab34可促进整合素β3的降解。因此，Rab34在Y247位被Src磷酸化。一个模拟磷酸化形式的Rab34的突变体(Rab34Y247D)促进细胞迁移和侵袭。重要的是，Rab34的酪氨酸磷酸化在悬浮的细胞中受到抑制，并随着细胞的重新黏附而增加。此外，Rab34Y247D还促进细胞黏附，促进整合素β3的内吞和循环。这些结果揭示了Rab34在乳腺癌细胞的迁移和侵袭中的作用及其与肿瘤转移的关系，并提供了一种新的机制，即Rab34的酪氨酸磷酸化通过调节整合素β3的内吞、稳定和循环来调节细胞的迁移、侵袭和黏附。
The small GTPase Rab34 regulates spatial distribution of the lysosomes, secretion, and macropinocytosis. In this study, we found that Rab34 is over-expressed in aggressive breast cancer cells, implying a potential role of Rab34 in breast cancer. Silencing Rab34 by shRNA inhibits cell migration, invasion, and adhesion of breast cancer cells. Rab34 specifically binds to the cytoplasmic tail of integrin β3, and depletion of Rab34 promotes the degradation of integrin β3. Interestingly, EGF induces the translocation of Rab34 to the membrane ruffle, which is greatly enhanced by the expression of Src kinase. Accordingly, Rab34 is tyrosine phosphorylated by Src at Y247 residue. A mutant mimicking phosphorylated form of Rab34 (Rab34Y247D) promotes cell migration and invasion. Importantly, the tyrosine phosphorylation of Rab34 is inhibited in cells in suspension, and increased with the cells re-adhesion. In addition, Rab34Y247D promotes cell adhesion, and enhances integrin β3 endocytosis and recycling. The results uncover a role of Rab34 in migration and invasion of breast cancer cells and its involvement in cancer metastasis, and provide a novel mechanism of tyrosine phosphorylation of Rab34 in regulating cell migration, invasion, and adhesion through modulating the endocytosis, stability, and recycling of integrin β3.