Threshold-controlled ubiquitination of the EGFR directs receptor fate

• Sara Sigismund ^[2] ; Veronica Algisi ^[2] ; Gilda Nappo ^[2] ; Alexia Conte ^[2] ; Roberta Pascolutti ^[2] ; Alessandro Cuomo ^[3] ; Tiziana Bonaldi ^[3] ; Elisabetta Argenzio ^[2] ; Lisette G G C Verhoef ^[2] ; Elena Maspero ^[2] ; Fabrizio Bianchi ^[3] ; Fabrizio Capuani ^[2] ; Andrea Ciliberto ^[2] ; Simona Polo ^[1] ; Pier Paolo Di Fiore ^[1]
  1. [1] University of Milan

     University of Milan

     Milán, Italia

     
  2. [2] IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
  3. [3] Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 32, Nº. 15, 2013, págs. 2140-2157
• Idioma: inglés
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  • 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.