Nature Medicine8, 1089 - 1097 (2002)
Published online: 9 September 2002; | doi:10.1038/nm763
Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice
Niall C. Tebbutt1, 5, Andrew S. Giraud2, 5, Melissa Inglese1, Brendan Jenkins1, Paul Waring3, Fiona J. Clay1, Sina Malki2, Barbara M. Alderman2, Dianne Grail1, Frédéric Hollande4, Joan K. Heath1
& Matthias Ernst1
1
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia
2
Department of Medicine, University of Melbourne, Western Hospital, Footscray, Victoria, Australia
3
Department of Pathology, Peter MacCallum Institute, East Melbourne, Victoria, Australia
4
Laboratoire de Signalisation Cellulaire Normale et Tumorale, Faculté de Pharmacie, Montpellier, France
5
N.C.T. and A.S.G. contributed equally to this study.
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. Gp130757F 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 (gp130STAT), 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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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.
