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

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

Author information

1
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.
2
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.
3
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.
4
Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
5
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.
6
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.
7
Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA.
8
Department of Medicine, VA San Diego Healthcare System, San Diego, California 92161, USA.
9
Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
10
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.
11
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
12
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.
13
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.
14
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.
15
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.

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.

PMID:
25731159
PMCID:
PMC4447318
DOI:
10.1038/nature14228
[Indexed for MEDLINE]
Free PMC Article

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