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Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling

Oncogene volume 30, pages 737–750 (2011)Cite this article

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Abstract

The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene had been isolated as an antagonist to RAS signaling; however, the mechanism of its action is not clear. In this study, the effect of loss of RECK function was assessed in various ways and cell systems. Successive cell cultivation of mouse embryonic fibroblasts (MEFs) according to 3T3 protocol revealed that the germline knockout of RECK confers accelerated cell proliferation and early escape from cellular senescence associated with downregulation of p19Arf, Trp53 and p21Cdkn1a. In contrast, short hairpin RNA-mediated depletion of RECK induced irreversible growth arrest along with several features of the Arf, Trp53 and Cdkn1a-dependent cellular senescence. Within 2 days of RECK depletion, we observed a transient increase in protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) phosphorylation associated with an upregulated expression of cyclin D1, p19Arf, Trp53, p21Cdkn1a and Sprouty 2. On further cultivation, RAS, AKT and ERK activities were then downregulated to a level lower than control, indicating that RECK depletion leads to a negative feedback to RAS signaling and subsequent cellular senescence. In addition, we observed that epidermal growth factor receptor (EGFR) activity was transiently upregulated by RECK depletion in MEFs, and continuously downregulated by RECK overexpression in colon cancer cells. These findings indicate that RECK is a novel modulator of EGFR signaling.

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Acknowledgements

We thank H Sato and T Muraguchi for critical reading of the paper; T Kamijo, P Leder, N Sharpless, S Itohara, Y Okada and M Seiki for providing the mice; M Seiki, T Sakamoto and T Nakano for providing cells; S Yano and K Matsumoto and S Higashiyama for providing the reagents; C Sugita for supporting mouse transfer; W Hung, K Lee and J Oh for encouragement; H Gu and A Nishimoto for technical assistance; and A Miyazaki and M Suzuki for secretarial assistance. SK thanks the JASSO scholarship for support. This work was supported by a Research Grant from the Princess Takamatsu Cancer Research Fund, Astellas Foundation for Research on Metabolic Disorders, the Takeda Science Foundation and the Japanese Ministry of Education, Culture, Sports, Science and Technology.

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Authors and Affiliations

  1. Division of Oncology and Molecular Biology, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan

    S Kitajima, Y Kido, A Shamma & C Takahashi

  2. Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan

    S Kitajima, T Miki, Y Takegami, M Noda, A Shamma & C Takahashi

  3. The 21st Century Center of Excellence Program, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan

    T Miki, A Shamma & C Takahashi

  4. Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX, USA

    T Miki

  5. Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan

    E Hara

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Kitajima, S., Miki, T., Takegami, Y. et al. Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling. Oncogene 30, 737–750 (2011). https://doi.org/10.1038/onc.2010.448

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