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FRS2β, a potential prognostic gene for non-small cell lung cancer, encodes a feedback inhibitor of EGF receptor family members by ERK binding

Oncogene volume 29, pages 3087–3099 (2010)Cite this article

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Abstract

An adaptor protein FRS2β inhibits epidermal growth factor-receptor (EGFR) tyrosine kinase without being phosphorylated at tyrosine residues after EGF stimulation. Although binding to ERK appears to be important for this inhibition, the precise molecular mechanisms and the role of FRS2β in signal transduction mediated by other EGFR family members, as well as its role in human cancer, remain unclear. In this study, we demonstrate that FRS2β inhibits anchorage-independent cell growth induced by oncogenic ErbB2, another member of EGFR family, and that it inhibits heterodimer formation between EGFR and ErbB2. We mapped the residues important for the FRS2β and ERK interaction to two docking (D) domain-like sequences on FRS2β and two aspartic acid residues in the common docking (CD) domain of ERK. Moreover, in response to EGF, ERK translocated to the plasma membrane in cells expressing FRS2β but not an FRS2β mutant in which four arginine residues in the D domains were replaced with alanines, suggesting that FRS2β serves as a plasma membrane anchor for activated ERK. Finally, a low mRNA expression level of FRS2β was significantly correlated with poor prognosis in a cohort of 60 non-small cell lung cancer patients. Therefore, we have identified the molecular mechanisms by which FRS2β acts as a feedback inhibitor of EGFR family members and suggest a role for FRS2β as a tumor suppressor.

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Acknowledgements

We are grateful to Dr Toshio Kitamura for valuable reagents for retrovirus expression system and Dr Tadashi Yamamoto for NIH3T3 cells expressing oncogenic ErbB2 and for expression vectors for ErbB2 and VE mutant. This work was supported by grants from the Ministry of Health, Labor and Welfare of Japan for the 3rd-term Comprehensive 10-year Strategy for Cancer Control; from the Naito Foundation; and Cell Science Research Foundation to NG.

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Author notes

  1. D Iejima, Y Minegishi, K Takenaka and A Siswanto: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Systems Biomedical Technology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan

    D Iejima, Y Minegishi, A Siswanto, M Watanabe & N Gotoh

  2. Department of Thoracic Surgery, Kyoto University Medical School, Kyoto, Japan

    K Takenaka & F Tanaka

  3. Department of Thoracic Surgery, Koseikai Takeda Hospital, Kyoto, Japan

    K Takenaka

  4. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Minato-ku, Tokyo, Japan

    A Siswanto & T Watanabe

  5. Cellular Biochemistry Laboratory, RIKEN, Wako, Saitama, Japan

    L Huang

  6. Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, Japan

    F Tanaka

  7. Department of Pathology, Tokyo Medical University, Tokyo, Japan

    M Kuroda

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  1. D Iejima
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  2. Y Minegishi
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Correspondence to N Gotoh.

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Supplementary Information accompanies the paper on the Oncogene website

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Iejima, D., Minegishi, Y., Takenaka, K. et al. FRS2β, a potential prognostic gene for non-small cell lung cancer, encodes a feedback inhibitor of EGF receptor family members by ERK binding. Oncogene 29, 3087–3099 (2010). https://doi.org/10.1038/onc.2010.69

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