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Mig6 is a negative regulator of EGF receptor–mediated skin morphogenesis and tumor formation

Nature Medicine volume 12, pages 568–573 (2006)Cite this article

An Erratum to this article was published on 01 July 2006

Abstract

The growing number of recently identified negative feedback regulators of receptor tyrosine kinases (RTKs) highlights the importance of signal attenuation and modulation for correct signaling outcome. Mitogen-inducible gene 6 (Mig6 also known as RALT or Gene 33) is a multiadaptor protein thought to be involved in the regulation of RTK and stress signaling1,2,3. Here, we show that deletion of the mouse gene encoding Mig6 (designated Errfi1, which stands for ERBB receptor feedback inhibitor 1) causes hyperactivation of endogenous epidermal growth factor receptor (EGFR) and sustained signaling through the mitogen-activated protein kinase (MAPK) pathway, resulting in overproliferation and impaired differentiation of epidermal keratinocytes. Furthermore, Errfi1−/− mice develop spontaneous tumors in various organs and are highly susceptible to chemically induced formation of skin tumors. A tumor-suppressive role for Mig6 is supported by our finding that MIG6 is downregulated in various human cancers. Inhibition of endogenous Egfr signaling with the Egfr inhibitor gefitinib (Iressa) or replacement of wild-type Egfr with the kinase-deficient protein encoded by the hypomorphic Egfrwa2 allele completely rescued skin defects in Errffi1−/− * mice. Carcinogen-induced tumors displayed by Errfi1−/− mice were highly sensitive to gefitinib. These results indicate that Mig6 is a specific negative regulator of Egfr signaling in skin morphogenesis and is a novel tumor suppressor of Egfr-dependent carcinogenesis.

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Figure 1: Genetic knockout of the mouse gene Errfi1 causes skin pathology.
Figure 2: Egfr-dependent hyperproliferation, impaired differentiation of epidermis in Errfi1−/− mice and sustained Egfr-mediated Mapk activation in Errfi1−/− epidermal keratinocytes.
Figure 3: Responsiveness of Errffi1−/− mice to two-stage carcinogenesis.
Figure 4: Spontaneous neoplasia in Errfi1−/− mice, downregulation of MIG6 in human cancer and inverse correlation of MIG6 expression levels with EGFR autophosphorylation.

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Notes

  1. NOTE: In the version of this article initially published, Errfi1 was incorrectly referred to as Erffi1 in several instances, and in Figure 1h the middle panels of the immunoblot were labeled Egf instead of Hgf. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank J. Bailey for technical help with embryonic stem cell work; M. Boesl and the Max-Planck Institute transgenic service for the generation of Errfi1−/− mice; the MPI animal services for mouse husbandry; G. Keri for providing bioassay standard Iressa; and S. Werner and T. Mäkinen for discussions. I.F. was supported by an EMBO long-term fellowship and O.K. by an Erwin Schrödinger fellowship. This work was supported by the Max-Planck Society and by a grant from Boehringer Ingelheim (to R.K. and A.U.).

Author information

Author notes

  1. Guido Pantè

    Present address: Clintec GmbH, Königsallee 106, 40215, Düsseldorf, Germany

Authors and Affiliations

  1. Department of Molecular Neurobiology, Max-Planck Institute of Neurobiology, Klopferspitz 18, Martinsried, 82152, Germany

    Ingvar Ferby, Guido Pantè & Rüdiger Klein

  2. Department of Molecular Biology, Max-Planck Institute of Biochemistry, Klopferspitz 18, Martinsried, 82152, Germany

    Markus Reschke, Pjotr Knyazev & Axel Ullrich

  3. Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Klopferspitz 18, Martinsried, 82152, Germany

    Oliver Kudlacek & Reinhard Fässler

  4. Department of Pathology, University of Erlangen-Nürnberg, Krankenhausstr. 8-10, Erlangen, 91054, Germany

    Kerstin Amann

  5. Boehringer Ingelheim Austria GmbH, Dr. Boehringer-Gasse 5-11, Vienna, 1121, Austria

    Wolfgang Sommergruber & Norbert Kraut

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Correspondence to Rüdiger Klein.

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Supplementary information

Supplementary Fig. 1

Gene-targeting strategy and delayed eyelid opening in Mig6−/−mice. (PDF 1988 kb)

Supplementary Fig. 2

Suprabasal proliferation, impaired differentiation and unaltered integrin expression in Mig6−/− skin. (PDF 582 kb)

Supplementary Fig. 3

Sustained ErbB mediated MAPK activation and increased cell motility of Mig6−/− keratinocytes. (PDF 1516 kb)

Supplementary Fig. 4

The hypomorphic Egfrwa2 allele rescues the Mig6−/− epidermal phenotype. (PDF 713 kb)

Supplementary Fig. 5

Mig6−/− mice develop papillomas at sites of injury. (a) Mig6−/− mice develop papillomas on the tagged ear at 3 months of age (8 out of 12 mice). (PDF 529 kb)

Supplementary Fig. 6

Mechanism of Gefitinib-induced papilloma regression. (PDF 2060 kb)

Supplementary Fig. 7

Histology of various hyperplastic lesions in Mig6−/− mice. (PDF 2184 kb)

Supplementary Fig. 8

Inverse correlation between MIG6 and HER3 mRNA levels in melanoma cell lines. (PDF 609 kb)

Supplementary Table 1

Occurrence of tumors or hyperplasia in Errffi1–/– mice (PDF 56 kb)

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Ferby, I., Reschke, M., Kudlacek, O. et al. Mig6 is a negative regulator of EGF receptor–mediated skin morphogenesis and tumor formation. Nat Med 12, 568–573 (2006). https://doi.org/10.1038/nm1401

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