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

S. Anastasi, M. F. Baietti, Y. Frosi, S. Alemà, O. Segatto

Research output: Contribution to journalArticlepeer-review

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 the αI 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.

Original languageEnglish
Pages (from-to)7833-7846
Number of pages14
JournalOncogene
Volume26
Issue number57
DOIs
Publication statusPublished - Dec 13 2007

Keywords

  • EGFR
  • Feedback inhibition
  • MIG6
  • Negative signalling
  • RALT
  • Tumour suppression

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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