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Rab34 regulates adhesion, migration, and invasion of breast cancer cells

Oncogenevolume 37pages36983714 (2018) | Download Citation

Abstract

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.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (No.31371353 and No.31671478) and International Science & Technology Cooperation Program of China (No.2013DFG32730). The cDNA of integrin β1 and integrin β3 were kindly provided by Dr. Jiahuai Han (State Key Laboratory of Cellular Stress Biology, Xiamen University, China).

Author contributions

SL and XX conducted most of the experiments and analyzed the results. CY and ZY conducted experiments on cell metastasis in vivo. TR and FR completed assays on cancer tissues. QH, JL, and ZY provided technical supports. HW involved in the ideas and paper writing. WT conceived the idea for the project, experiments design, and wrote the paper.

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Author notes

  1. These authors contributed equally: L. Sun, X. Xu.

Affiliations

  1. School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, 361005, China

    • Lixiang Sun
    • , Xiaohui Xu
    • , Yongjun Chen
    • , Yuxia Zhou
    • , Hantian Qiu
    • , Liting Jin
    • , Wenyi Zhang
    • , Rong Fan
    • , Wanjin Hong
    •  & Tuanlao Wang
  2. Third Institute of Oceanography, State Oceanic Administration, Xiamen, 361005, China

    • Ran Tan
  3. Institute of Molecular and Cell Biology, A STAR (Agency of Science, Technology and Research), 61 Biopolis Drive, Singapore, 138673, Singapore

    • Wanjin Hong

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The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Wanjin Hong or Tuanlao Wang.

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DOI

https://doi.org/10.1038/s41388-018-0202-7