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The membrane-anchored metalloproteinase regulator RECK stabilizes focal adhesions and anterior–posterior polarity in fibroblasts

Oncogene volume 28, pages 1454–1464 (2009)Cite this article

Abstract

Accumulating evidence indicates that Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored matrix metalloproteinase regulator, plays crucial roles in mammalian development and tumor suppression. Its mechanisms of action at the single cell level, however, remain largely unknown. In mouse fibroblasts, RECK is abundant around the perinuclear region, membrane ruffles and cell surface. Cells lacking Reck show decreased spreading, ambiguous anterior–posterior (AP) polarity, and increased speed and decreased directional persistence in migration; these characteristics are also found in transformed fibroblasts and fibrosarcoma cells with low RECK expression. RECK-deficient cells fail to form discrete focal adhesions, have increased levels of GTP-bound Rac1 and Cdc42, and a marked decrease in the level of detyrosinated tubulin, a hallmark of stabilized microtubules. RECK-deficient cells also show elevated gelatinolytic activity and decreased fibronectin fibrils. The phenotype of RECK-deficient cells is largely suppressed when the cells are plated on fibronectin-coated substrates. These findings suggest that RECK regulates pericellular extracellular matrix degradation, thereby allowing the cells to form proper cell–substrate adhesions and to maintain AP polarity during migration; this mechanism is compromised in malignant cells.

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Acknowledgements

We are grateful to Dr Susan Creig for the GFP-vinculin expression vector, to Drs Shuh Narumiya, Alicia Arroyo and Motoharu Seiki for critical reading of the paper, and to the anonymous reviewer for suggesting the use of GM130 for analysing cell polarity. We also thank Emi Nishimoto, Takashi Kawai, Aiko Nishimoto and Aki Miyazaki for their technical and secretarial assistance, Akira Omura for his technical advice and So-ichiro Noda for his help in data analysis. This work was supported by JSPS Grant-in-Aid for Creative Scientific Research and MEXT Grant-in-Aid on Priority Areas.

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Authors and Affiliations

  1. Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan

    Y Morioka, T Matsuzaki, S Shi, H Kitayama & M Noda

  2. Department of Pharmacology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan

    J Monypenny

  3. Department of Life Science and Engineering, Harbin Institute of Technology, Harbin, China

    S Shi

  4. Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya, Japan

    D B Alexander

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  1. Y Morioka
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  6. H Kitayama
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  7. M Noda
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Correspondence to M Noda.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Morioka, Y., Monypenny, J., Matsuzaki, T. et al. The membrane-anchored metalloproteinase regulator RECK stabilizes focal adhesions and anterior–posterior polarity in fibroblasts. Oncogene 28, 1454–1464 (2009). https://doi.org/10.1038/onc.2008.486

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