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

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.

References

  1. Makkinje, A. et al. Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress. J. Biol. Chem. 275, 17838–17847 (2000).

    Article  CAS  Google Scholar 

  2. 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 

  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. Chu, D.T., Davis, C.M., Chrapkiewicz, N.B. & Granner, D.K. Reciprocal regulation of gene transcription by insulin. Inhibition of the phosphoenolpyruvate carboxykinase gene and stimulation of gene 33 in a single cell type. J. Biol. Chem. 263, 13007–13011 (1988).

    CAS  PubMed  Google Scholar 

  5. Wick, M., Burger, C., Funk, M. & Muller, R. Identification of a novel mitogen-inducible gene (mig-6): regulation during G1 progression and differentiation. Exp. Cell Res. 219, 527–535 (1995).

    Article  CAS  Google Scholar 

  6. Fiorini, M. et al. Expression of RALT, a feedback inhibitor of ErbB receptors, is subjected to an integrated transcriptional and post-translational control. Oncogene 21, 6530–6539 (2002).

    Article  CAS  Google Scholar 

  7. 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 

  8. Pante, G. et al. Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth. J. Cell Biol. 171, 337–348 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Vassar, R. & Fuchs, E. Transgenic mice provide new insights into the role of TGF-α during epidermal development and differentiation. Genes Dev. 5, 714–727 (1991).

    Article  CAS  Google Scholar 

  11. Cook, P.W. et al. Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype. J. Clin. Invest. 100, 2286–2294 (1997).

    Article  CAS  Google Scholar 

  12. Fuchs, E. & Green, H. Changes in keratin gene expression during terminal differentiation of the keratinocyte. Cell 19, 1033–1042 (1980).

    Article  CAS  Google Scholar 

  13. Candi, E., Schmidt, R. & Melino, G. The cornified envelope: a model of cell death in the skin. Nat. Rev. Mol. Cell Biol. 6, 328–340 (2005).

    Article  CAS  Google Scholar 

  14. Watt, F.M. Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J. 21, 3919–3926 (2002).

    Article  CAS  Google Scholar 

  15. 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 

  16. McCawley, L.J., Li, S., Wattenberg, E.V. & Hudson, L.G. Sustained activation of the mitogen-activated protein kinase pathway. A mechanism underlying receptor tyrosine kinase specificity for matrix metalloproteinase-9 induction and cell migration. J. Biol. Chem. 274, 4347–4353 (1999).

    Article  CAS  Google Scholar 

  17. Zeigler, M.E., Chi, Y., Schmidt, T. & Varani, J. Role of ERK and JNK pathways in regulating cell motility and matrix metalloproteinase 9 production in growth factor-stimulated human epidermal keratinocytes. J. Cell. Physiol. 180, 271–284 (1999).

    Article  CAS  Google Scholar 

  18. Luetteke, N.C. et al. The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase. Genes Dev. 8, 399–413 (1994).

    Article  CAS  Google Scholar 

  19. Werner, S. & Grose, R. Regulation of wound healing by growth factors and cytokines. Physiol. Rev. 83, 835–870 (2003).

    Article  CAS  Google Scholar 

  20. Vassar, R., Hutton, M.E. & Fuchs, E. Transgenic overexpression of transforming growth factor α bypasses the need for c-Ha-ras mutations in mouse skin tumorigenesis. Mol. Cell. Biol. 12, 4643–4653 (1992).

    Article  CAS  Google Scholar 

  21. Dlugosz, A.A. et al. Targeted disruption of the epidermal growth factor receptor impairs growth of squamous papillomas expressing the v-ras(Ha) oncogene but does not block in vitro keratinocyte responses to oncogenic ras. Cancer Res. 57, 3180–3188 (1997).

    CAS  PubMed  Google Scholar 

  22. DiGiovanni, J., Rho, O., Xian, W. & Beltran, L. Role of the epidermal growth factor receptor and transforming growth factor α in mouse skin carcinogenesis. Prog. Clin. Biol. Res. 387, 113–138 (1994).

    CAS  PubMed  Google Scholar 

  23. Zhang, Y.W. et al. Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease. Proc. Natl. Acad. Sci. USA 102, 11740–11745 (2005).

    Article  CAS  Google Scholar 

  24. Amatschek, S. et al. Tissue-wide expression profiling using cDNA subtraction and microarrays to identify tumor-specific genes. Cancer Res. 64, 844–856 (2004).

    Article  CAS  Google Scholar 

  25. Ogunbiyi, O.A. et al. Prognostic value of chromosome 1p allelic loss in colon cancer. Gastroenterology 113, 761–766 (1997).

    Article  CAS  Google Scholar 

  26. Koshikawa, K. et al. Allelic imbalance at 1p36 in the pathogenesis of human hepatocellular carcinoma. Hepatogastroenterology 51, 186–191 (2004).

    PubMed  Google Scholar 

  27. Tseng, R.C. et al. Genomewide loss of heterozygosity and its clinical associations in non small cell lung cancer. Int. J. Cancer 117, 241–247 (2005).

    Article  CAS  Google Scholar 

  28. Savontaus, M., Metsranta, M. & Vuorio, E. Retarded skeletal development in transgenic mice with a type II collagen mutation. Am. J. Pathol. 149, 2169–2182 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Krampert, M. et al. ADAMTS1 proteinase is upregulated in wounded skin and regulates migration of fibroblasts and endothelial cells. J. Biol. Chem. 280, 23844–23852 (2005).

    Article  CAS  Google Scholar 

  30. Shen-Ong, G.L., Feng, Y. & Troyer, D.A. Expression profiling identifies a novel α-methylacyl-CoA racemase exon with fumarate hydratase homology. Cancer Res. 63, 3296–3301 (2003).

    CAS  PubMed  Google Scholar 

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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.).

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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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