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

Abstract

Summary Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members whose expression is elevated in many diseases, including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). We show 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 classic gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signaling 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 upon receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.

Role of Src Family Kinases in Regulation of Intestinal Epithelial Homeostasis

“…The Rho family GTPases Rac and Rho are thought to contribute to YAP activation by oncogenic mutants of GNAQ in a manner dependent on actin polymerization (46). Phosphorylation of YAP at Tyr 357 by c-Src increases the stability of the protein, and this action of c-Src has been implicated in the promotion of IEC proliferation (47). Such tyrosine phosphorylation by c-Src of YAP was demonstrated to occur under mucosal injury of the intestine (47).…”

“…Phosphorylation of YAP at Tyr 357 by c-Src increases the stability of the protein, and this action of c-Src has been implicated in the promotion of IEC proliferation (47). Such tyrosine phosphorylation by c-Src of YAP was demonstrated to occur under mucosal injury of the intestine (47). In contrast, we failed to detect the phosphorylation of YAP at Tyr 357 in crypts isolated from the small intestine of either control or Csk CKO mice under the steady-state condition (see Fig.…”

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

“…Thus, the intracellular signaling activated by the proinflammatory cytokines, growth factors, or by the intrinsic proliferative signals may interact and co-operate to efficiently conduct the repair process. Accordingly, a recent study has shown that gp130, a co-receptor of IL-6, may activate both YAP and Notch and contribute to the tissue repair of the colitic mucosa [77].…”

The nucleo-junctional interplay of the cellular prion protein: A new partner in cancer-related signaling pathways?

“…SFK activity (Src and Yes) has been shown recently to favor YAP nuclear translocation. 39 It would be important to determine how, upon cancer-associated dismantling of cell-cell junction, PrP c , which interacts with YAP, could modulate its activation as well. In order to determine how the mechanisms that involve PrP c in cancer process and EMT are integrated, the analysis of the respective proportions and subcellular localizations of PrP c , Src, b-catenin, TCF, g-catenin, YAP and TAZ in a large-scale study of human tumors would be of great interest.…”