Molecular basis for multimerization in the activation of the epidermal growth factor receptor

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Abstract

The epidermal growth factor receptor (EGFR) is activated by dimerization, but activation also generates higher-order multimers, whose nature and function are poorly understood. We have characterized ligand-induced dimerization and multimerization of EGFR using single-molecule analysis, and show that multimerization can be blocked by mutations in a specific region of Domain IV of the extracellular module. These mutations reduce autophosphorylation of the C-terminal tail of EGFR and attenuate phosphorylation of phosphatidyl inositol 3-kinase, which is recruited by EGFR. The catalytic activity of EGFR is switched on through allosteric activation of one kinase domain by another, and we show that if this is restricted to dimers, then sites in the tail that are proximal to the kinase domain are phosphorylated in only one subunit. We propose a structural model for EGFR multimerization through self-association of ligand-bound dimers, in which the majority of kinase domains are activated cooperatively, thereby boosting tail phosphorylation.

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Yongjian Huang

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Shashank Bharill

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Deepti Karandur

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Sean M Peterson

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Morgan Marita

Department of Chemistry, University of Akron, Akron, United States

Competing interests
No competing interests declared.
Xiaojun Shi

Department of Chemistry, University of Akron, Akron, United States

Competing interests
No competing interests declared.
Megan J Kaliszewski

Department of Chemistry, University of Akron, Akron, United States

Competing interests
No competing interests declared.
Adam W Smith

Department of Chemistry, University of Akron, Akron, United States

Competing interests
No competing interests declared.
Ehud Y Isacoff

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
John Kuriyan

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

For correspondence
jkuriyan@mac.com

Competing interests
John Kuriyan, Senior editor, eLife.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Our Xenopus protocol has been approved by Institutional Animal Care and Use Committee (IACUC) of the University of California.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.