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Cited by 474Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesDigestive system and related health

Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice

Tebbutt, Niall C., Giraud, Andrew S., Inglese, Melissa, Jenkins, Brendan, Waring, Paul, Clay, Fiona J., Malki, Sina, Alderman, Barbara M. +4 more·2002·Nature Medicine
DOI 10.1038/nm763
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Abstract

The intracellular signaling mechanisms that specify tissue-specific responses to the interleukin-6 (IL-6) family of cytokines are not well understood. Here, we evaluated the functions of the two major signaling pathways, the signal transducers and activators of transcription 1 and 3 (STAT1/3) and the Src-homology tyrosine phosphatase 2 (SHP2)-Ras-ERK, emanating from the common signal transducer, gp130, in the gastrointestinal tract. Gp130(757F) mice, with a 'knock-in' mutation abrogating SHP2-Ras-ERK signaling, developed gastric adenomas by three months of age. In contrast, mice harboring the reciprocal mutation ablating STAT1/3 signaling (gp130(Delta STAT)), or deficient in IL-6-mediated gp130 signaling (IL-6(-/-) mice), showed impaired colonic mucosal wound healing. These gastrointestinal phenotypes are highly similar to the phenotypes exhibited by mice deficient in trefoil factor 1 (pS2/TFF1) and intestinal trefoil factor (ITF)/TFF3, respectively, and corresponded closely with the capacity of the two pathways to stimulate transcription of the genes encoding pS2/TFF1 and ITF/TFF3. We propose a model whereby mucosal wound healing depends solely on activation of STAT1/3, whereas gastric hyperplasia ensues when the coordinated activation of the STAT1/3 and SHP2-Ras-ERK pathways is disrupted.

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Crossref · 10.1038/nm763

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  • gp130Y757F/Y757F mice show hyper-activation of STAT3 and develop gastric hyperplasia resembling human early-stage gastric cancer.

    “Another knock-in mouse strain (gp130Y757F/Y757F mice) having the point mutation Y759F in murine gp130 also shows the hyper-activation of STAT3 and develops gastric hyperplasia resembling human early-stage gastric cancer (64, 256).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [256]

  • F759 mice take about 1 year to develop arthritis, while gp130Y757F/Y757F mice show hyperproliferative lesions in the stomach mucosa as early as 6 weeks.

    “In fact, it takes about 1 year for F759 mice to develop arthritis, while gp130Y757F/Y757F mice show hyperproliferative lesions in the stomach mucosa as early as 6 weeks (256).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [256]

  • A similar pathway involving inflammation, IL-6 and STAT3 is downstream of H. pylori in the generation of stomach cancer.

    “Interestingly, a similar pathway involving inflammation, IL-6 and STAT3 is downstream of H. pylori in the generation of stomach cancer38.”

    From Inflammation and cancer (2002) · cites this paper as [38]

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Authors
Tebbutt, N. C., Giraud, A. S., Inglese, M., Jenkins, B., Waring, P., Clay, F. J., Malki, S., Alderman, B. M., Grail, D., Hollande, F., Heath, J. K., & Ernst, M.
Affiliations
  • The Royal Melbourne Hospital (AU)
  • The University of Melbourne (AU)
  • Peter MacCallum Cancer Centre (AU)
  • Université de Montpellier (FR)
Corresponding author
Ernst, Matthias
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2002-09-09
Volume
8
Issue
10
Pages
1089-1097
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm763
OpenAlex
W2084150021
Cited by
474
References
45
Citations by year
2026: 7 · 2025: 10 · 2024: 9 · 2023: 10 · 2022: 15 · 2021: 26 · 2020: 11 · 2019: 14 · 2018: 12 · 2017: 13 · 2016: 19 · 2015: 19 · 2014: 27 · 2013: 26 · 2012: 29
FWCI
10.94
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
Keywords
gp130, SHP2, STAT1/3 signaling, interleukin-6 family cytokines, TFF1, TFF3, gastrointestinal homeostasis, gastric adenoma, Ras/ERK signaling, transcriptional regulation, IL-6 deficiency
MeSH terms
Trefoil Factor-2, Trefoil Factor-3, Adenoma, Animals, Cell Line, Colon, Digestive System Physiological Phenomena, DNA-Binding Proteins, Gastric Mucosa, Gene Expression Regulation, Growth Substances, Homeostasis, Intestinal Mucosa, Membrane Glycoproteins, Mice, Transgenic, Mucins, Muscle Proteins, Neuropeptides, Peptides, Proteins, Spleen, Stomach, Stomach Neoplasms, Wound Healing, Signal Transduction, Transcriptional Activation, Trans-Activators, Antigens, CD, Interleukin-6, Protein Tyrosine Phosphatases, Interleukin-11, Mitogen-Activated Protein Kinases, Intracellular Signaling Peptides and Proteins, STAT1 Transcription Factor, Cytokine Receptor gp130, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Phosphatase 2

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