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

Nature. 2015 Mar 5;519(7541):57-62. doi: 10.1038/nature14228. Epub 2015 Feb 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Body Weight
  • Cell Cycle Proteins
  • Cell Differentiation
  • Cell Proliferation
  • Cytokine Receptor gp130 / metabolism*
  • Disease Models, Animal
  • Enzyme Activation
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • HEK293 Cells
  • Homeostasis
  • Humans
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Inflammatory Bowel Diseases / metabolism
  • Inflammatory Bowel Diseases / pathology
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Mice
  • Phosphoproteins / metabolism*
  • Proto-Oncogene Proteins c-yes / metabolism
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Receptors, Notch / metabolism
  • Regeneration*
  • Signal Transduction
  • Up-Regulation

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • Receptors, Notch
  • Yap1 protein, mouse
  • Cytokine Receptor gp130
  • Proto-Oncogene Proteins c-yes
  • Proto-Oncogene Proteins pp60(c-src)