Nature 519, 57–62 (05 March 2015)
Received 07 April 2014
Accepted 09 January 2015
Published online 25 February 2015
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 & Michael Karin
Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USAInflammation 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.