Distinct interactions stabilize EGFR dimers and higher-order oligomers in cell membranes
Krishna C. Mudumbi,
Eric A. Burns,
David J. Schodt,
Zaritza O. Petrova,
Anatoly Kiyatkin,
Lucy W. Kim,
Emma M. Mangiacapre,
Irais Ortiz-Caraveo,
Hector Rivera Ortiz,
Chun Hu,
Kumar D. Ashtekar,
Keith A. Lidke,
Diane S. Lidke,
Mark A. Lemmon
Affiliations
Krishna C. Mudumbi
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA; Corresponding author
Eric A. Burns
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA; Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
David J. Schodt
Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87106, USA
Zaritza O. Petrova
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA
Anatoly Kiyatkin
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA
Lucy W. Kim
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA
Emma M. Mangiacapre
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA
Irais Ortiz-Caraveo
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA; Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Hector Rivera Ortiz
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA
Chun Hu
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA
Kumar D. Ashtekar
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA
Keith A. Lidke
Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87106, USA
Diane S. Lidke
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA; Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Corresponding author
Mark A. Lemmon
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University West Campus, West Haven, CT 06516, USA; Corresponding author
Summary: The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase with important roles in many cellular processes as well as in cancer and other diseases. EGF binding promotes EGFR dimerization and autophosphorylation through interactions that are well understood structurally. How these dimers relate to higher-order EGFR oligomers seen in cell membranes, however, remains unclear. Here, we used single-particle tracking (SPT) and Förster resonance energy transfer imaging to examine how each domain of EGFR contributes to receptor oligomerization and the rate of receptor diffusion in the cell membrane. Although the extracellular region of EGFR is sufficient to drive receptor dimerization, we find that the EGF-induced EGFR slowdown seen by SPT requires higher-order oligomerization—mediated in part by the intracellular tyrosine kinase domain when it adopts an active conformation. Our data thus provide important insight into the interactions required for higher-order EGFR assemblies involved in EGF signaling.
