TY - JOUR
T1 - Threshold-controlled ubiquitination of the EGFR directs receptor fate
AU - Sigismund, Sara
AU - Algisi, Veronica
AU - Nappo, Gilda
AU - Conte, Alexia
AU - Pascolutti, Roberta
AU - Cuomo, Alessandro
AU - Bonaldi, Tiziana
AU - Argenzio, Elisabetta
AU - Verhoef, Lisette G G C
AU - Maspero, Elena
AU - Bianchi, Fabrizio
AU - Capuani, Fabrizio
AU - Ciliberto, Andrea
AU - Polo, Simona
AU - Di Fiore, Pier Paolo
PY - 2013/7/31
Y1 - 2013/7/31
N2 - 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.
AB - 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.
KW - EGFR
KW - endocytosis
KW - ubiquitination
UR - http://www.scopus.com/inward/record.url?scp=84881446387&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84881446387&partnerID=8YFLogxK
U2 - 10.1038/emboj.2013.149
DO - 10.1038/emboj.2013.149
M3 - Article
C2 - 23799367
AN - SCOPUS:84881446387
VL - 32
SP - 2140
EP - 2157
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 15
ER -