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The Sprouty-related protein, Spred, inhibits cell motility, metastasis, and Rho-mediated actin reorganization

Oncogene volume 23, pages 5567–5576 (2004)Cite this article

Abstract

Sprouty and the Sprouty-related protein, Spred (Sprouty-related Ena/vasodilator-stimulated phosphoprotein homology-1 (EVH1) domain-containing protein), inhibit Ras-dependent extracellular signal-regulated kinase (ERK) signaling induced by a variety of growth factors. Since Sprouty proteins have been shown to inhibit not only ERK activation but also cell migration, we postulated that Spreds also inhibit cellular migration. Using stably highly metastatic LM8 cells infected with the Spred1-Sendai virus vector, we demonstrated that Spred1 inhibits the metastasis of LM8 cells in nude mice. Spred1 overexpression also inhibited migration of cells in vitro in response to chemokines, CCL19 and CCL21. We also found that Spred1 overexpression dissolved actin-stress fibers. Both EVH1 domain and C-terminal Sprouty-related domain were required for actin reassembly. Spred1 and Spred2 suppressed constitutively activated RhoA (V14RhoA)-induced stress fiber formation and serum response factor activation. Spred1 bound to activated RhoA, but not cdc42 and Rac. Spred1 also inhibited chemokine-induced RhoA activation and active RhoA-induced Rho-kinase activation. These data suggest that Spreds are key regulators of RhoA-mediated cell motility and signal transduction. Furthermore, our study suggests that the induction of Spreds could be a novel strategy for preventing cancer cell metastasis.

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Acknowledgements

We thank Ms Kawabata-Honda and S Sata for excellent technical assistance, Dr Kaibuchi (Nagoya University) for Rho, Rac, and cdc42 plasmids, Dr Narumiya (Kyoto University) for GST-RBD and Rock plasmids, Ms Arifuku and Ms Yamaura for manuscript preparation. This work was supported by Special Grants-in-Aid from the Ministry of Education, Science, Technology, Sports, and Culture of Japan, the Japan Health Science Foundation, the Human Frontier Science Program, the Japan Research Foundation for Clinical Pharmacology, and the Uehara Memorial Foundation.

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Authors and Affiliations

  1. Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Kanta Miyoshi, Toru Wakioka, Hitomi Nishinakamura, Masaki Kamio, Lu Yang & Akihiko Yoshimura

  2. Department of Orthopedic Surgery, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan

    Kanta Miyoshi & Setsuro Komiya

  3. DNAVEC Research Inc., Tsukuba, Ibaraki, Japan

    Makoto Inoue & Mamoru Hasegawa

  4. Department of Pathology Graduate School of Medical Sciences, Division of Pathophysiological and Experimental Pathology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Yoshikazu Yonemitsu

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  1. Kanta Miyoshi
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Correspondence to Akihiko Yoshimura.

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Miyoshi, K., Wakioka, T., Nishinakamura, H. et al. The Sprouty-related protein, Spred, inhibits cell motility, metastasis, and Rho-mediated actin reorganization. Oncogene 23, 5567–5576 (2004). https://doi.org/10.1038/sj.onc.1207759

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