Abstract
Cell migration driven by the epidermal growth factor receptor (EGFR) propels morphogenesis1 and involves reorganization of the actin cytoskeleton2. Although de novo transcription precedes migration3,4, transcript identity remains largely unknown. Through their actin-binding domains, tensins link the cytoskeleton to integrin-based adhesion sites5. Here we report that EGF downregulates tensin-3 expression, and concomitantly upregulates cten, a tensin family member that lacks the actin-binding domain6. Knockdown of cten or tensin-3, respectively, impairs or enhances mammary cell migration. Furthermore, cten displaces tensin-3 from the cytoplasmic tail of integrin β1, thereby instigating actin fibre disassembly. In invasive breast cancer, cten expression correlates not only with high EGFR and HER2, but also with metastasis to lymph nodes. Moreover, treatment of inflammatory breast cancer patients with an EGFR/HER2 dual-specificity kinase inhibitor significantly downregulated cten expression. In conclusion, a transcriptional tensin-3–cten switch may contribute to the metastasis of mammary cancer.
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Acknowledgements
We thank Kenneth Yamada, Shin Lin and Mark Ginsberg for plasmids; Dalia Seger and Hadassa Degani for guidance with xenografts; Miriam Eisenstein for structure prediction; and Benjamin Geiger and Alexander Bershadsky for critical comments. Our laboratory is supported by research grants from the Israel Cancer Research Fund, the German Israel Foundation, the Prostate Cancer Foundation, the European Commission and the National Cancer Institute (grants CA72981 and CA102537). Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. T.S. was supported in part by the Ridgefield Foundation, the Israel Science Fund and the European Commission (EC FP6). S.C. is the recipient of a grant from Fundação para Ciência e Tecnologia (FCT), Lisboa, Portugal.
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Katz, M., Amit, I., Citri, A. et al. A reciprocal tensin-3–cten switch mediates EGF-driven mammary cell migration. Nat Cell Biol 9, 961–969 (2007). https://doi.org/10.1038/ncb1622
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DOI: https://doi.org/10.1038/ncb1622
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