A gp130–Src–YAP module links inflammation to epithelial regeneration

Koji Taniguchi, Li-Wha Wu, Sergei I. Grivennikov, Petrus R. de Jong, Ian Lian, Fa-Xing Yu, Kepeng Wang, Samuel B. Ho, Brigid S. Boland, John T. Chang, William J. Sandborn, Gary Hardiman, Eyal Raz, Yoshihiko Maehara, Akihiko Yoshimura, Jessica Zucman-Rossi, Kun-Liang Guan and Michael Karin ()
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Koji Taniguchi: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA
Li-Wha Wu: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA
Sergei I. Grivennikov: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA
Petrus R. de Jong: University of California, San Diego, La Jolla, California 92093, USA
Ian Lian: University of California, San Diego, La Jolla, California 92093, USA
Fa-Xing Yu: University of California, San Diego, La Jolla, California 92093, USA
Kepeng Wang: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA
Samuel B. Ho: VA San Diego Healthcare System
Brigid S. Boland: Inflammatory Bowel Disease Center, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA
John T. Chang: Inflammatory Bowel Disease Center, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA
William J. Sandborn: Inflammatory Bowel Disease Center, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA
Gary Hardiman: Medical University of South Carolina
Eyal Raz: University of California, San Diego, La Jolla, California 92093, USA
Yoshihiko Maehara: Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Akihiko Yoshimura: Keio University School of Medicine, Tokyo 160-8582, Japan
Jessica Zucman-Rossi: Inserm, UMR 1162, Génomique fonctionnelle des tumeurs solides, IUH, Paris 75010, France
Kun-Liang Guan: University of California, San Diego, La Jolla, California 92093, USA
Michael Karin: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA

Nature, 2015, vol. 519, issue 7541, 57-62

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14228

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