Phosphorylated EGFR Dimers Are Not Sufficient to Activate Ras

Publication date: 6 March 2018
Source:Cell Reports, Volume 22, Issue 10
Author(s): Samantha I. Liang, Bettina van Lengerich, Kelsie Eichel, Minkwon Cha, David M. Patterson, Tae-Young Yoon, Mark von Zastrow, Natalia Jura, Zev J. Gartner
Growth factor binding to EGFR drives conformational changes that promote homodimerization and transphosphorylation, followed by adaptor recruitment, oligomerization, and signaling through Ras. Whether specific receptor conformations and oligomerization states are necessary for efficient activation of Ras is unclear. We therefore evaluated the sufficiency of a phosphorylated EGFR dimer to activate Ras without growth factor by developing a chemical-genetic strategy to crosslink and "trap" full-length EGFR homodimers on cells. Trapped dimers become phosphorylated and recruit adaptor proteins at stoichiometry equivalent to that of EGF-stimulated receptors. Surprisingly, these phosphorylated dimers do not activate Ras, Erk, or Akt. In the absence of EGF, phosphorylated dimers do not further oligomerize or reorganize on cell membranes. These results suggest that a phosphorylated EGFR dimer loaded with core signaling adapters is not sufficient to activate Ras and that EGFR ligands contribute to conformational changes or receptor dynamics necessary for oligomerization and efficient signal propagation through the SOS-Ras-MAPK pathway.

Graphical abstract

Teaser

Liang et al. demonstrate that the recruitment of key signaling adapters to stable phosphorylated EGFR dimers is not sufficient for the activation of Ras and its downstream pathways. Binding of EGFR ligands induces conformational changes and receptor dynamics necessary for oligomerization and efficient signal propagation through the SOS-Ras-MAPK pathway.


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