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

Koji Taniguchi; Li-Wha Wu; Sergei I Grivennikov; Petrus R de Jong; Ian Lian; Fa-Xing Yu; Kepeng Wang; Samuel B Ho; Brigid S Boland; John T Chang; William J Sandborn; Gary Hardiman; Eyal Raz; Yoshihiko Maehara; Akihiko Yoshimura; Jessica Zucman-Rossi; Kun-Liang Guan; Michael Karin

doi:10.1038/nature14228

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.

Authors

Koji Taniguchi¹, Li-Wha Wu², Sergei I Grivennikov³, Petrus R de Jong⁴, Ian Lian⁵, Fa-Xing Yu⁶, Kepeng Wang⁷, Samuel B Ho⁸, Brigid S Boland⁹, John T Chang⁹, William J Sandborn⁹, Gary Hardiman¹⁰, Eyal Raz⁴, Yoshihiko Maehara¹¹, Akihiko Yoshimura¹², Jessica Zucman-Rossi¹³, Kun-Liang Guan¹⁴, Michael Karin¹⁵

Affiliations

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.

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
YAP-Signaling Proteins

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding