Threshold-controlled ubiquitination of the EGFR directs receptor fate

Sara Sigismund, Veronica Algisi, Gilda Nappo, Alexia Conte, Roberta Pascolutti, Alessandro Cuomo, Tiziana Bonaldi, Elisabetta Argenzio, Lisette G G C Verhoef, Elena Maspero, Fabrizio Bianchi, Fabrizio Capuani, Andrea Ciliberto, Simona Polo, Pier Paolo Di Fiore

Research output: Contribution to journalArticlepeer-review


How the cell converts graded signals into threshold-activated responses is a question of great biological relevance. Here, we uncover a nonlinear modality of epidermal growth factor receptor (EGFR)-activated signal transduction, by demonstrating that the ubiquitination of the EGFR at the PM is threshold controlled. The ubiquitination threshold is mechanistically determined by the cooperative recruitment of the E3 ligase Cbl, in complex with Grb2, to the EGFR. This, in turn, is dependent on the simultaneous presence of two phosphotyrosines, pY1045 and either one of pY1068 or pY1086, on the same EGFR moiety. The dose-response curve of EGFR ubiquitination correlate precisely with the non-clathrin endocytosis (NCE) mode of EGFR internalization. Finally, EGFR-NCE mechanistically depends on EGFR ubiquitination, as the two events can be simultaneously re-engineered on a phosphorylation/ubiquitination-incompetent EGFR backbone. Since NCE controls the degradation of the EGFR, our findings have implications for how the cell responds to increasing levels of EGFR signalling, by varying the balance of receptor signalling and degradation/attenuation.

Original languageEnglish
Pages (from-to)2140-2157
Number of pages18
JournalEMBO Journal
Issue number15
Publication statusPublished - Jul 31 2013


  • EGFR
  • endocytosis
  • ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)


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