Phosphorylated EGFR Dimers Are Not Sufficient to Activate Ras
Samantha I. Liang,
Bettina van Lengerich,
Kelsie Eichel,
Minkwon Cha,
David M. Patterson,
Tae-Young Yoon,
Mark von Zastrow,
Natalia Jura,
Zev J. Gartner
Affiliations
Samantha I. Liang
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA; Program in Biochemistry and Molecular Biology, University of California, San Francisco, San Francisco, CA, USA
Bettina van Lengerich
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA
Kelsie Eichel
Program in Biochemistry and Molecular Biology, University of California, San Francisco, San Francisco, CA, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
Minkwon Cha
Department of Physics, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea; Center for Nanomedicine, Institute for Basic Science (IBS), Yonsei University, Seoul 30722, South Korea; Yonsei-IBS Institute, Yonsei University, Seoul 30722, South Korea
David M. Patterson
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
Tae-Young Yoon
Center for Nanomedicine, Institute for Basic Science (IBS), Yonsei University, Seoul 30722, South Korea; Yonsei-IBS Institute, Yonsei University, Seoul 30722, South Korea; Department of Biological Sciences, Seoul National University, Seoul 08826, South Korea
Mark von Zastrow
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
Natalia Jura
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA; Corresponding author
Zev J. Gartner
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA; Center for Cellular Construction, University of California, San Francisco, San Francisco, CA, USA; Corresponding author
Summary: 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. : 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. Keywords: EGFR signaling, chemical-genetic dimerization, Ras-MAPK signaling, spatial reorganization, EGFR nanoclusters
