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PTPN3 suppresses lung cancer cell invasiveness by counteracting Src-mediated DAAM1 activation and actin polymerization

Oncogene volume 38, pages 7002–7016 (2019)Cite this article

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Abstract

Cancer cell migration plays a crucial role during the metastatic process. Reversible tyrosine phosphorylation by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) have been implicated in the regulation of cancer cell migration and invasion. However, the underlying mechanisms have not been fully elucidated. Here, we show that depletion of the FERM and PDZ domain-containing protein tyrosine phosphatase PTPN3 enhances lung cancer cell migration/invasion and metastasis by promoting actin filament assembly and focal adhesion dynamics. We further identified Src and DAAM1 (dishevelled associated activator of morphogenesis 1) as interactors of PTPN3. DAAM1 is a formin-like protein involved in the regulation of actin cytoskeletal remodeling. PTPN3 inhibits Src activity and Src-mediated phosphorylation of Tyr652 on DAAM1. The tyrosine phosphorylation of DAAM1 is essential for DAAM1 homodimer formation and actin polymerization. Ectopic expression of a DAAM1 phosphodeficient mutant inhibited F-actin assembly and suppressed lung cancer cell migration and invasion. Our findings reveal a novel mechanism by which reversible tyrosine phosphorylation of DAAM1 by Src and PTPN3 regulates actin dynamics and lung cancer invasiveness.

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Acknowledgements

We thank Ruey-Hwa Chen, Raymond Habas, Jean-Cheng Kuo, Jai Prakash Singh, and Tzu-Ching Meng for helpful discussion and reagents. We thank Chin-Chun Hung for confocal and cell imaging assistance; Suh-Yuen Liang for the bioinformatic support; Min-Feng Hsu for structural assistance; the National RNAi Core Facility for shRNAs; Academia Sinica Common Mass Spectrometry Facilities for mass spectrometric assistance; IBC Histopathology Core Facility for tissue processing and histology. We are grateful to Cindy Lee for English editing. This work was supported by the Ministry of Science and Technology of Taiwan (NSC102-2311-B-001-027-MY3) and Academia Sinica.

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  1. Institute of Biological Chemistry, Academia Sinica, Taipei, 115, Taiwan

    Meng-Yen Li, Wen-Hsin Peng, Yu-Ling Lin & Guang-Chao Chen

  2. Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, 106, Taiwan

    Ya-Min Chang, Geen-Dong Chang & Guang-Chao Chen

  3. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, 115, Taiwan

    Chien-Hsun Wu & Han-Chung Wu

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G-CC and M-YL conceived the study and designed the experiments. M-YL, C-HW, W-HP, Y-MC, Y-LL and G-DC conducted the experiments. G-DC and H-CW contributed to materials and methods and edited the paper. G-CC and M-YL analyzed the data and wrote the paper.

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Correspondence to Guang-Chao Chen.

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Li, MY., Peng, WH., Wu, CH. et al. PTPN3 suppresses lung cancer cell invasiveness by counteracting Src-mediated DAAM1 activation and actin polymerization. Oncogene 38, 7002–7016 (2019). https://doi.org/10.1038/s41388-019-0948-6

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