EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization

Kathryn M. Ferguson, Mitchell B. Berger, Jeannine M. Mendrola, Hyun Soo Cho, Daniel J. Leahy, Mark A. Lemmon

Research output: Contribution to journalArticlepeer-review

625 Citations (Scopus)


Epidermal growth factor (EGF) receptor is the prototype of the ErbB (HER) family receptor tyrosine kinases (RTKs), which regulate cell growth and differentiation and are implicated in many human cancers. EGF activates its receptor by inducing dimerization of the 621 amino acid EGF receptor extracellular region. We describe the 2.8 Å resolution crystal structure of this entire extracellular region (sEGFR) in an unactivated state. The structure reveals an autoinhibited configuration, where the dimerization interface recently identified in activated sEGFR structures is completely occluded by intramolecular interactions. To activate the receptor, EGF binding must promote a large domain rearrangement that exposes this dimerization interface. This contrasts starkly with other RTK activation mechanisms and suggests new approaches for designing ErbB receptor antagonists.

Original languageEnglish
Pages (from-to)507-517
Number of pages11
JournalMolecular Cell
Issue number2
Publication statusPublished - 2003 Feb 1

Bibliographical note

Funding Information:
We thank T. Garrett, T. Burgess, S. Yokoyama, and their colleagues for discussions and for generously sharing information prior to publication; J. Schlessinger, G. Van Duyne, and members of the Lemmon laboratory for valuable discussions and comments on the manuscript; M. Becker for assistance with beamline X-25 at the National Synchrotron Light Source, Brookhaven; and the staff of beamline F1 at the Cornell High-Energy Synchrotron Source (CHESS), which is supported by the NSF and the NIH. This work was supported by National Cancer Institute grants R01-CA79992 and R21-CA87182 (to M.A.L.), K01-CA092246 (to K.M.F.), R01-CA090466 (to D.J.L.); fellowships from the U.S. Army Breast Cancer Research Program to K.M.F. (DAMD17-98-1-8228) and M.B.B. (DAMD17-01-1-0363), and from the American Cancer Society (PF-00-174-01-TBE) to J.M.M.; as well as funds from the Damon Runyon Cancer Research Fund (M.A.L.), the Howard Hughes Medical Institute (D.J.L.), and the Burroughs Wellcome Foundation (K.M.F.).

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization'. Together they form a unique fingerprint.

Cite this