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Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface


Members of the epidermal growth factor receptor family (EGFR/ERBB1, ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are key targets for inhibition in cancer therapy1. Critical for activation is the formation of an asymmetric dimer by the intracellular kinase domains, in which the carboxy-terminal lobe (C lobe) of one kinase domain induces an active conformation in the other2. The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 (refs 3–5). Crystal structures of complexes between the EGFR kinase domain and a fragment of MIG6 show that a 25-residue epitope (segment 1) from MIG6 binds to the distal surface of the C lobe of the kinase domain. Biochemical and cell-based analyses confirm that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface. A longer MIG6 peptide that is extended C terminal to segment 1 has increased potency as an inhibitor of the activated EGFR kinase domain, while retaining a critical dependence on segment 1. We show that signalling by EGFR molecules that contain constitutively active kinase domains still requires formation of the asymmetric dimer, underscoring the importance of dimer interface blockage in MIG6-mediated inhibition.

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Figure 1: Structure of the EGFR kinase domain/MIG6(segment 1).
Figure 2: Binding and inhibition of EGFR by MIG6(segment 1).
Figure 3: Inhibition of EGFR kinase activity by MIG6(segments 1–2).
Figure 4: A double-headed mechanism for EGFR inhibition by MIG6.

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The atomic coordinates are deposited at the Protein Data Bank under accession codes 2RF9, 2RFD and 2RFE.


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We thank X. Cao and A. Fisher for cell culture support; D. King for mass spectrometry; the staff at beamlines 8.2.1 and 12.3.1 of the Advanced Light Source for technical support; and M. Seeliger, S. Deindl, P. Pellicena, J. Gureasko, S. Jacques and other members in the Kuriyan and Cole groups for technical help and discussions. We thank T. Miller for discussions on ACK1. This work is supported in part by grants from the NCI to J.K. and from NIH to P.A.C. R.B. is supported by the Susan G. Komen Breast Cancer Foundation.

Author Contributions J.K., X.Z. and P.A.C. designed the project. X.Z. performed biochemical and cell-based assays and crystallography work. K.A.P. and R.B. synthesized peptides. N.J. performed some biochemical and cell-based assays. J.K. and X.Z. wrote the manuscript.

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Correspondence to John Kuriyan.

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The file contains Supplementary Notes, Supplementary Tables 1-2, Supplementary Figures 1-7 with Legends and additional references. (PDF 2393 kb)

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Zhang, X., Pickin, K., Bose, R. et al. Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface. Nature 450, 741–744 (2007).

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