Distinct Interactions Stabilize EGFR Dimers and Higher-Order Oligomers in Cell Membranes

Authors

• 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.
• 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.Follow
• 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.Follow

Document Type

Article

Publication Date

1-23-2024

Abstract

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.

Recommended Citation

Mudumbi KC, Burns EA, Schodt DJ, Petrova ZO, Kiyatkin A, Kim LW, Mangiacapre EM, Ortiz-Caraveo I, Rivera Ortiz H, Hu C, Ashtekar KD, Lidke KA, Lidke DS, Lemmon MA. Distinct interactions stabilize EGFR dimers and higher-order oligomers in cell membranes. Cell Rep. 2024 Jan 23;43(1):113603. doi: 10.1016/j.celrep.2023.113603. Epub 2023 Dec 20. PMID: 38117650; PMCID: PMC10835193.