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

Nature volume 450, pages 741–744 (2007)Cite this article

Abstract

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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Protein Data Bank

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

References

  1. Hynes, N. E. & Lane, H. A. ERBB receptors and cancer: the complexity of targeted inhibitors. Nature Rev. Cancer 5, 341–354 (2005)

    Article  CAS  Google Scholar 

  2. Zhang, X. et al. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125, 1137–1149 (2006)

    Article  CAS  Google Scholar 

  3. Hackel, P. O., Gishizky, M. & Ullrich, A. Mig-6 is a negative regulator of the epidermal growth factor receptor signal. Biol. Chem. 382, 1649–1662 (2001)

    Article  CAS  Google Scholar 

  4. Xu, D., Makkinje, A. & Kyriakis, J. M. Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function. J. Biol. Chem. 280, 2924–2933 (2005)

    Article  CAS  Google Scholar 

  5. Fiorentino, L. et al. Inhibition of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain. Mol. Cell. Biol. 20, 7735–7750 (2000)

    Article  CAS  Google Scholar 

  6. Wood, E. R. et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 64, 6652–6659 (2004)

    Article  CAS  Google Scholar 

  7. Jeffrey, P. D. et al. Mechanism of CDK activation revealed by the structure of a cyclinA–CDK2 complex. Nature 376, 313–320 (1995)

    Article  ADS  CAS  Google Scholar 

  8. Ballaro, C. et al. Targeted expression of RALT in mouse skin inhibits epidermal growth factor receptor signalling and generates a Waved-like phenotype. EMBO Rep. 6, 755–761 (2005)

    Article  CAS  Google Scholar 

  9. Ferby, I. et al. Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation. Nature Med. 12, 568–573 (2006)

    Article  CAS  Google Scholar 

  10. Zhang, Y. W. et al. Evidence that MIG-6 is a tumor-suppressor gene. Oncogene 26, 269–276 (2007)

    Article  CAS  Google Scholar 

  11. Shen, F. et al. Activated Cdc42-associated kinase 1 is a component of EGF receptor signaling complex and regulates EGF receptor degradation. Mol. Biol. Cell 18, 732–742 (2007)

    Article  CAS  Google Scholar 

  12. Anastasi, S. et al. Feedback inhibition by RALT controls signal output by the ErbB network. Oncogene 22, 4221–4234 (2003)

    Article  CAS  Google Scholar 

  13. Anastasi, S. et al. The evolutionarily conserved EBR module of RALT/MIG6 mediates suppression of the EGFR catalytic activity. Oncogene advanced online publication. doi: 10.1038/sj.onc.1210590 (18 June 2007)

  14. Stamos, J., Sliwkowski, M. X. & Eigenbrot, C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem. 277, 46265–46272 (2002)

    Article  CAS  Google Scholar 

  15. Depetris, R. S. et al. Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14. Mol. Cell 20, 325–333 (2005)

    Article  CAS  Google Scholar 

  16. Lei, M., Robinson, M. A. & Harrison, S. C. The active conformation of the PAK1 kinase domain. Structure 13, 769–778 (2005)

    Article  CAS  Google Scholar 

  17. Reynolds, A. R. et al. EGFR activation coupled to inhibition of tyrosine phosphatases causes lateral signal propagation. Nature Cell Biol. 5, 447–453 (2003)

    Article  CAS  Google Scholar 

  18. Ichinose, J., Murata, M., Yanagida, T. & Sako, Y. EGF signalling amplification induced by dynamic clustering of EGFR. Biochem. Biophys. Res. Commun. 324, 1143–1149 (2004)

    Article  CAS  Google Scholar 

  19. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004)

    Article  CAS  Google Scholar 

  20. Sordella, R., Bell, D. W., Haber, D. A. & Settleman, J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305, 1163–1167 (2004)

    Article  ADS  CAS  Google Scholar 

  21. Conti, E. & Kuriyan, J. Crystallographic analysis of the specific yet versatile recognition of distinct nuclear localization signals by karyopherin α. Structure 8, 329–338 (2000)

    Article  CAS  Google Scholar 

  22. Wedegaertner, P. B. & Gill, G. N. Activation of the purified protein tyrosine kinase domain of the epidermal growth factor receptor. J. Biol. Chem. 264, 11346–11353 (1989)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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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Author notes

  1. Xuewu Zhang & Ron Bose

    Present address: Present addresses: Department of Pharmacology and Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas 75390, USA (X.Z.); Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA (R.B.).,

Authors and Affiliations

  1. Department of Molecular and Cell Biology, and Department of Chemistry, and Howard Hughes Medical Institute, California Institute for Quantitative Sciences, University of California, Berkeley, California 94720, USA,

    Xuewu Zhang, Natalia Jura & John Kuriyan

  2. Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA,

    Kerry A. Pickin, Ron Bose & Philip A. Cole

  3. Physical Biosciences Division, Lawrence Berkeley National Laboratory Berkeley, California 94720, USA,

    John Kuriyan

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  1. Xuewu Zhang
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Corresponding author

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). https://doi.org/10.1038/nature05998

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