ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor

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Abstract

The orphan receptor tyrosine kinase ErbB2 (also known as HER2 or Neu) transforms cells when overexpressed1, and it is an important therapeutic target in human cancer2,3. Structural studies4,5 have suggested that the oncogenic (and ligand-independent) signalling properties of ErbB2 result from the absence of a key intramolecular ‘tether’ in the extracellular region that autoinhibits other human ErbB receptors, including the epidermal growth factor (EGF) receptor6. Although ErbB2 is unique among the four human ErbB receptors6,7, here we show that it is the closest structural relative of the single EGF receptor family member in Drosophila melanogaster (dEGFR). Genetic and biochemical data show that dEGFR is tightly regulated by growth factor ligands8, yet a crystal structure shows that it, too, lacks the intramolecular tether seen in human EGFR, ErbB3 and ErbB4. Instead, a distinct set of autoinhibitory interdomain interactions hold unliganded dEGFR in an inactive state. All of these interactions are maintained (and even extended) in ErbB2, arguing against the suggestion that ErbB2 lacks autoinhibition. We therefore suggest that normal and pathogenic ErbB2 signalling may be regulated by ligands in the same way as dEGFR. Our findings have important implications for ErbB2 regulation in human cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor.

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Figure 1: Autoinhibition of ErbB receptors.
Figure 2: The unactivated dEGFR extracellular region closely resembles sErbB2.
Figure 3: Ligand binding breaks autoinhibitory interactions between domains I and II common to s-dEGFR, s-hEGFR and sErbB2.

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Primary accessions

Protein Data Bank

Data deposits

The structure for s-dEGFRΔV has been deposited in the Protein Data Bank under accession number 3I2T.

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Acknowledgements

We thank members of the Lemmon and Ferguson laboratories, K. Ferguson, G. Van Duyne, C. Abrams and J. Shorter for advice and comments on the manuscript; Z. Bu for assistance with collecting SAXS data; and R. Gillilan of MacCHESS for help with SAXS data collection and processing at CHESS beamline G1. Crystallographic results were obtained in research conducted at the GM/CA Collaborative Access Team at the Advanced Photon Source (APS), supported with funds from the National Cancer Institute and National Institute of General Medical Science. This study was supported by grants from the NIH (to M.A.L.). D.E.K. was supported by a Predoctoral fellowship from the US Army Breast Cancer Research Program. D.A. was supported by an NIH Postdoctoral Training Grant and a Postdoctoral Fellowship from the Damon Runyon Cancer Research Foundation.

Author Contributions D.A., D.E.K. and M.A.L. conceived and designed the project. D.E.K. established initial expression and purification procedures for s-dEGFR variants and relevant ligands. D.A. was responsible for designing s-dEGFR constructs used in this study and executed all biophysical studies, crystallization and data collection. D.A. also solved and refined the s-dEGFRΔV structure. D.A. and M.A.L. interpreted data and wrote the manuscript.

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Correspondence to Mark A. Lemmon.

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This file contains Supplementary Figures S1-S7 with Legends, Supplementary Tables 1-3 and Supplementary References. (PDF 1114 kb)

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Alvarado, D., Klein, D. & Lemmon, M. ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor. Nature 461, 287–291 (2009) doi:10.1038/nature08297

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