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Met-induced membrane blebbing leads to amoeboid cell motility and invasion

Oncogene volume 33, pages 1788–1798 (2014)Cite this article

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Abstract

Met tyrosine kinase has been implicated in tumorigenesis and metastasis; its overexpression and deregulation is often observed in cancer. Although Met's functions in cell motility has been studied extensively, its involvement in bleb-based, amoeboid motility is yet to be determined. The aim of this work is to study the role of Met in amoeboid cell motility and invasion. We show that aggressive breast cancer cells expressing high levels of endogenous Met, as well as HEK293T cells over expressing fluorescent Met, exhibit constitutive, ligand-independent Met activation, leading to Met-dependent membrane blebbing and amoeboid cell motility; HEK293T cells over expressing fluorescent Met were able to invade in three-dimensional matrix. Hyper-activated Met mutant significantly enhances blebbing and cell motility. Met inhibition by either a Met-specific inhibitor or by exogenous expression of a dominant-negative Met remarkably repressed membrane blebbing and invasion. Inhibition of Rho signaling pathway by a ROCK inhibitor also represses Met-induced blebbing, suggesting that Met regulates the blebbing machinery through Rho-ROCK pathway, which controls the actin–myosin contractile force. Either de-polymerization or hyper-polymerization of the actin cytoskeleton abrogates Met-induced blebbing, signifying that actin polymerization has a role in halting and retracting Met-induced mature blebs. Indeed, when blebs retract, membrane wrinkles containing high levels of Met and actin are generated, indicating localized formation of Met-signaling microdomains. We suggest that this bleb-based activity is induced by amplification of Met signaling in unique membrane domains generated by bleb retraction. Our results indicate that Met-induced blebbing has an important role in cell detachment, amoeboid motility and invasion ability, which are utilized by cancer cells for migration and metastasis.

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Acknowledgements

We thank Professor Iafa Keydar for T47D cells and Dr Joyce Taylor-Papadimitriou for HB2 cells. We also thank Dr Yifat Merbl (Harvard medical school) for her critical review of this manuscript. This work was supported by research grants from the Breast Cancer Research Foundation, the United States-Israel Binational Science Foundation and the Federico Foundation Grants.

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  1. Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    A Laser-Azogui, T Diamant-Levi, S Israeli, Y Roytman & I Tsarfaty

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Correspondence to I Tsarfaty.

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Laser-Azogui, A., Diamant-Levi, T., Israeli, S. et al. Met-induced membrane blebbing leads to amoeboid cell motility and invasion. Oncogene 33, 1788–1798 (2014). https://doi.org/10.1038/onc.2013.138

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