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The evolutionarily conserved EBR module of RALT/MIG6 mediates suppression of the EGFR catalytic activity

Oncogene volume 26, pages 7833–7846 (2007)Cite this article

Abstract

Physiological signalling by the epidermal growth factor receptor (EGFR) controls developmental processes and tissue homeostasis, whereas aberrant EGFR activity drives oncogenic cell transformation. Under normal conditions, the EGFR must therefore generate outputs of defined strength and duration. To this aim, cells balance EGFR activity via different modalities of negative signalling. Increasing attention is being drawn on transcriptionally controlled feedback inhibitors of EGFR, namely RALT/MIG6, LRIG1, SOCS4 and SOCS5. Genetic studies in mice have revealed the essential role of Ralt/Mig6 in regulating Egfr-driven skin morphogenesis and tumour formation, yet the mechanisms through which RALT abrogates EGFR activity are still undefined. We report that RALT suppresses EGFR function by inhibiting its catalytic activity. The evolutionarily conserved ErbB-binding region (EBR) is necessary and sufficient to carry out RALT-dependent suppression of EGFR kinase activityin vitro and in intact cells. The mechanism involves binding of the EBR to the 953RYLVIQ958 sequence, which is located in theαI helix of the EGFR kinase and has been shown to participate in allosteric control of EGFR catalytic activity. Our results uncover a novel mechanism of temporal regulation of EGFR activity in vertebrate organisms.

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Acknowledgements

We thank V Federici for ERBB2/RALT co-IP studies, M Fanciulli, C Gaetano, A Musacchio, S Giordano, P Pisu, S Polo, Y Yarden and A Zingoni for reagents, PG Natali for support, L Sibilio for help with PDB analysis and R Fraioli for antibody purification. OS is supported by MIUR-FIRB, the Italian Ministry of Health and AIRC. S Alemà is supported by MIUR-FIRB and AIRC.

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  1. M F Baietti and Y Frosi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Oncology, Laboratory of Immunology, Regina Elena Cancer Institute, Rome, Italy

    S Anastasi, M F Baietti, Y Frosi & O Segatto

  2. Institute of Cell Biology, CNR, Monterotondo, Italy

    S Alemà

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  1. S Anastasi
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  2. M F Baietti
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  3. Y Frosi
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  5. O Segatto
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Correspondence to S Anastasi or O Segatto.

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

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Anastasi, S., Baietti, M., Frosi, Y. et al. The evolutionarily conserved EBR module of RALT/MIG6 mediates suppression of the EGFR catalytic activity. Oncogene 26, 7833–7846 (2007). https://doi.org/10.1038/sj.onc.1210590

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