The interleukin (IL)-6 family of cytokines activates gp130 signaling and plays essential roles in colonic inflammation and inflammation-induced tumorigenesis. It is reported that acute inflammation promotes tissue repair and regeneration, but the molecular mechanisms remains to be unknown. Here, to investigate the role of the IL-6 family of cytokines in tissue repair and regeneration, we have generated villin-gp130Act transgenic mice expressing constitutively active gp130 under villin promoter. The intestine of the gp130Act transgenic mice shows hyperproliferation and aberrant differentiation of the epithelium independently of STAT3 activation, and the mice are resistant to mucosal injury. We have found that gp130 can activate YAP and Notch through Src family kinase (SFK) activation independently of the JAK-STAT3 pathway. In addition to the JAK-STAT3 pathway, the SFK-YAP pathway is important for intestinal homeostasis and regeneration. This new finding might be helpful for regenerative medicine.