Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice.
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.
Tebbutt
Niall C
NC
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Giraud
Andrew S
AS
Inglese
Melissa
M
Jenkins
Brendan
B
Waring
Paul
P
Clay
Fiona J
FJ
Malki
Sina
S
Alderman
Barbara M
BM
Grail
Dianne
D
Hollande
Frédéric
F
Heath
Joan K
JK
Ernst
Matthias
M
D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003106:Colon / Q000378:metabolism / Q000473:pathology; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004068:Digestive System Physiological Phenomena; D005753:Gastric Mucosa / Q000378:metabolism; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis; D017370:Interleukin-11 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D054648:Protein Phosphatase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013270:Stomach / Q000166:cytology / Q000473:pathology; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D014945:Wound Healing
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D006133:Growth Substances; C494200:Il6st protein, mouse; D017370:Interleukin-11; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; D011506:Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C082495:TFF3 protein, human; C099037:TFF3 protein, rat; D015534:Trans-Activators; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D050822:Cytokine Receptor gp130; D020928:Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C516727:Ptpn11 protein, rat