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Abstract

Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.

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ArrayExpress

Data deposits

Microarray data reported here have been deposited in the ArrayExpress database under accession E-MEXP-E-MTAB-2400.

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Acknowledgements

We thank D. Pan and S. Akira for Yapfl/fl and Stat3fl/fl mice, respectively. We also thank D. L. Gumucio for a plasmid containing the 12.4-kb villin promoter, T. Sato, H. Clevers and Y. Hippo for protocols describing intestinal organoid culture, C. Kuo for R-spondin1-producing cells, D. Huszar for AZD1480, F. Schaper for plasmids, L. Eckmann for advice, A. Umemura, H. Nakagawa, H. Ogata, E. J. Park, G. Y. Yu, J. Font-Burgada, D. Dhar, J. Kim and E. Seki for providing liver samples, J. Zhao, T. Meerloo, Y. Jones, L. Gapuz, R. Ly, N. Varki, D. Aki, N. Hiramatsu, T. Moroishi, Y. Endo, H. Nishinakamura, A. Chang and T. Lee for technical advice and assistance, and Cell Signaling, Santa Cruz Biotechnology and GeneTex for antibodies. This work was supported by Postdoctoral Fellowship for Research Abroad and Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science, a Uehara Memorial Foundation Fellowship, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Kanae Foundation for the Promotion of Medical Science to K.T.; a traveling grant NSC-101-2918-I-006-005 and a research grant NSC-103-2320-B-006-032 by National Science Council of Taiwan to L.-W.W.; NIH R00DK088589, FCCC-Temple University Nodal grant, AACR-Landon Innovator Award in Tumor Microenvironment, and the Pew Scholar in Biomedical Sciences Program for S.I.G.; a CCFA fellowship (RFA2927) to P.R.d.J.; Croucher Foundation and China Postdoctoral Science Foundation to K.W.; by the Research Service of the Department of Veterans Affairs to S.B.H.; by the NIH and the UCSD Digestive Disease Research Center Grant to J.T.C. and W.J.S.; by the NIH EY022611 and CA132809 to K.-L.G.; and by the NIH CA118165-09 and AACR to M.K., who is an American Cancer Society Research Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.

Author information

Affiliations

  1. Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA

    • Koji Taniguchi
    • , Li-Wha Wu
    • , Sergei I. Grivennikov
    • , Kepeng Wang
    •  & Michael Karin
  2. Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, California 92093, USA

    • Koji Taniguchi
    • , Ian Lian
    • , Fa-Xing Yu
    • , Kun-Liang Guan
    •  & Michael Karin
  3. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan

    • Koji Taniguchi
    •  & Yoshihiko Maehara
  4. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan

    • Koji Taniguchi
    •  & Akihiko Yoshimura
  5. Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan

    • Li-Wha Wu
  6. Fox Chase Cancer Center, Cancer Prevention and Control Program, Philadelphia, Pennsylvania 19111, USA

    • Sergei I. Grivennikov
  7. Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA

    • Petrus R. de Jong
    •  & Eyal Raz
  8. Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA

    • Ian Lian
    • , Fa-Xing Yu
    • , Kun-Liang Guan
    •  & Michael Karin
  9. Department of Biology, Lamar University, PO Box 10037, Beaumont, Texas 77710, USA

    • Ian Lian
  10. Children’s Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China

    • Fa-Xing Yu
  11. Department of Medicine, VA San Diego Healthcare System, San Diego, California 92161, USA

    • Samuel B. Ho
  12. Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA

    • Brigid S. Boland
    • , John T. Chang
    •  & William J. Sandborn
  13. Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA

    • Gary Hardiman
  14. CSRC and BIMRC, San Diego State University, San Diego, California 92182, USA

    • Gary Hardiman
  15. Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan

    • Akihiko Yoshimura
  16. Inserm, UMR 1162, Génomique fonctionnelle des tumeurs solides, IUH, Paris 75010, France

    • Jessica Zucman-Rossi
  17. Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Medicine, Paris 75006, France

    • Jessica Zucman-Rossi

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Contributions

K.T. and M.K. conceived the project. K.T., L.-W.W., S.I.G., P.R.d.J., I.L., F.-X.Y., K.W., G.H. performed the experiments. K.T., L.-W.W., P.R.d.J, G.H. and M.K. analysed data. J.Z.-R. provided gp130 mutants, S.B.H., J.T.C., B.S.B. and W.J.S. provided human specimens, S.I.G., E.R., Y.M., A.Y., J.Z.-R. and K.-L.G. provided conceptual advice. K.T., L.-W.W. and M.K. wrote the manuscript, with all authors contributing to the writing and providing advice.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael Karin.

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https://doi.org/10.1038/nature14228

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