A gp130-Src-YAP module links inflammation to epithelial regeneration.
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.
1] Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA [2] Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, California 92093, USA [3] Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan [4] Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Koji
K
Taniguchi
1] Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA [2] Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
Li-Wha
LW
Wu
1] Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA [2] Fox Chase Cancer Center, Cancer Prevention and Control Program, Philadelphia, Pennsylvania 19111, USA.
Sergei I
SI
Grivennikov
Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Petrus R
PR
de Jong
1] Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, California 92093, USA [2] Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA [3] Department of Biology, Lamar University, PO Box 10037, Beaumont, Texas 77710, USA.
Ian
I
Lian
1] Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, California 92093, USA [2] Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA [3] Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Fa-Xing
FX
Yu
Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA.
Kepeng
K
Wang
Department of Medicine, VA San Diego Healthcare System, San Diego, California 92161, USA.
Samuel B
SB
Ho
Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Brigid S
BS
Boland
Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
John T
JT
Chang
Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
William J
WJ
Sandborn
1] Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA [2] CSRC and BIMRC, San Diego State University, San Diego, California 92182, USA.
Gary
G
Hardiman
Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Eyal
E
Raz
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Yoshihiko
Y
Maehara
1] Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan.
Akihiko
A
Yoshimura
1] Inserm, UMR 1162, Génomique fonctionnelle des tumeurs solides, IUH, Paris 75010, France [2] Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Medicine, Paris 75006, France.
Jessica
J
Zucman-Rossi
1] Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, California 92093, USA [2] Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
Kun-Liang
KL
Guan
1] Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA [2] Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, California 92093, USA [3] Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
Michael
M
Karin
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D051575:Proto-Oncogene Proteins c-yes / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D015854:Up-Regulation; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D051880:Receptors, Notch; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D050822:Cytokine Receptor gp130; D051575:Proto-Oncogene Proteins c-yes; D016392:Proto-Oncogene Proteins pp60(c-src)