Epithelial Tyrosine Phosphatase SHP-2 Protects against Intestinal Inflammation in Mice

Coulombe, Geneviève; Leblanc, Caroline; Cagnol, Sébastien; Maloum, Faïza; Lemieux, Etienne; Perreault, Nathalie; Feng, Gen‐Sheng; Boudreau, François; Rivard, Nathalie

doi:10.1128/mcb.00043-13

Cited by 37 publications

(74 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with our results, the hepatocyte-specific deletion of SHP-2 resulted in a marked increase in the strength of the inflammatory IL-6/STAT3 signal, which facilitated the development of hepatocellular carcinoma4. STAT3 was also hyperactivated in the colonic epithelium from mice with an intestinal epithelial cell-SHP-2 deletion25. Nguyen and colleagues investigated the impact of SHP-2 in T-cell biology by generating shp -2 flox/flox : Lck-Cre /+ mice, and found that conditional deletion of SHP-2 in thymocytes reduced expansion of CD4 + T cells and suppressed TCR signals26.…”

Section: Discussionsupporting

confidence: 89%

Loss of SHP-2 activity in CD4+ T cells promotes melanoma progression and metastasis

Zhang

Guo

Yang

et al. 2013

Sci Rep

View full text Add to dashboard Cite

The Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) has been reported to have both tumor-promoting and tumor-suppressing roles in tumorigenesis. However, the role of SHP-2 in tumor immunity remains unclear. Here we observed progressively lower levels of phosphorylated SHP-2 in tumor-associated CD4+ T cells during melanoma development in a murine model. Similarly, the levels of phosphorylated SHP-2 in the CD4+ T cells of human melanoma specimens revealed a decrease paralleling cancer development. The CD4+ T cell-specific deletion of SHP-2 promoted melanoma metastasis in mice. Furthermore, SHP-2 deficiency in CD4+ T cells resulted in the increased release of inflammatory cytokines, especially IL-6, and the enhanced accumulation of tumor-promoting myeloid-derived suppressor cells (MDSCs) in tumor-bearing mice. An IL-6-neutralizing antibody reduced MDSC accumulation and inhibited tumor growth in CD4+ T-cell-specific SHP-2-knockout mice. Our results suggest that SHP-2 in CD4+ T cells plays an important role in preventing melanoma progression and metastasis.

show abstract

Section: Discussionsupporting

confidence: 89%

Loss of SHP-2 activity in CD4+ T cells promotes melanoma progression and metastasis

Zhang

Guo

Yang

et al. 2013

Sci Rep

View full text Add to dashboard Cite

show abstract

“…We observed increased SHP2 expression within the pulmonary vasculature after retroorbital administration of SHP2 D61A cDNA, concomitant with attenuation of pulmonary edema formation. Given the ubiquitous distribution of SHP2 within the lung (58-60), we cannot discount that the protective role of SHP2 activation may be mediated by other cell types within the lung, which had taken up the injected cDNA, such as via tightening of epithelial junctions or diminishing the inflammatory response (61,62). However, given that overexpression of SHP2 D61A resulted in enhanced endothelial barrier function in vitro, and that we demonstrate SHP2 D61A overexpression in lung endothelial cells in vivo, our studies support the notion that SHP2 is protective against edema formation in the lung vasculature.…”

Section: Discussionmentioning

confidence: 99%

SH2 Domain-Containing Protein Tyrosine Phosphatase 2 and Focal Adhesion Kinase Protein Interactions Regulate Pulmonary Endothelium Barrier Function

Chichger

Braza

Duong

et al. 2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Enhanced protein tyrosine phosphorylation is associated with changes in vascular permeability through formation and dissolution of adherens junctions and regulation of stress fiber formation. Inhibition of the protein tyrosine phosphorylase SH2 domaincontaining protein tyrosine phosphatase 2 (SHP2) increases tyrosine phosphorylation of vascular endothelial cadherin and b-catenin, resulting in disruption of the endothelial monolayer and edema formation in the pulmonary endothelium. Vascular permeability is a hallmark of acute lung injury (ALI); thus, enhanced SHP2 activity offers potential therapeutic value for the pulmonary vasculature in diseases such as ALI, but this has not been characterized. To assess whether SHP2 activity mediates protection against edema in the endothelium, we assessed the effect of molecular activation of SHP2 on lung endothelial barrier function in response to the edemagenic agents LPS and thrombin. Both LPS and thrombin reduced SHP2 activity, correlated with decreased focal adhesion kinase (FAK) phosphorylation (Y 397 and Y 925 ) and diminished SHP2 protein-protein associations with FAK. Overexpression of constitutively active SHP2 (SHP2 D61A ) enhanced baseline endothelial monolayer resistance and completely blocked LPSand thrombin-induced permeability in vitro and significantly blunted pulmonary edema formation induced by either endotoxin (LPS) or Pseudomonas aeruginosa exposure in vivo. Chemical inhibition of FAK decreased SHP2 protein-protein interactions with FAK concomitant with increased permeability; however, overexpression of SHP2 D61A rescued the endothelium and maintained FAK activity and FAK-SHP2 protein interactions. Our data suggest that SHP2 activation offers the pulmonary endothelium protection against barrier permeability mediators downstream of the FAK signaling pathway. We postulate that further studies into the promotion of SHP2 activation in the pulmonary endothelium may offer a therapeutic approach for patients suffering from ALI.Keywords: endothelium; SH2 domain-containing protein tyrosine phosphatase 2; pulmonary edema; acute lung injury; focal adhesion kinase Clinical RelevanceThis work studies the mechanism through which SHP2 activation protects the endothelial barrier against injury. In settings of acute lung injury, activation of SHP2 may offer a novel therapeutic approach to treat pulmonary edema.Acute respiratory distress syndrome (ARDS) is a complex syndrome associated with severe arterial hypoxemia. Onset of ARDS results from several predisposing factors, such as pneumonia, pancreatitis, sepsis, and trauma. At present, patients suffering from ARDS are treated with mechanical ventilation; however, there are insufficient treatment options available, and

show abstract

“…Permeability was assessed with the fluorescent isothiocyanate (FITC)-labeled dextran method as described previously50. Mice were oral gavage with 60 mg/100g body weight of FITC-dextran (FD4, average molecular weight of 3,000–5,000, Sigma-Aldrich Canada Co., Oakville, ON) and sacrificed after 4 h. FITC concentration in the serum was quantified with a BioTek Synergy HT spectrometer plate reader (Winooski, VT) with excitation of the fluorophore at 492 nm and emission at 525 nm.…”

Section: Methodsmentioning

confidence: 99%

Gata4 is critical to maintain gut barrier function and mucosal integrity following epithelial injury

LePage

Bélanger

Jones

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

The intestinal epithelial barrier is critical to limit potential harmful consequences from exposure to deleterious luminal contents on the organism. Although this barrier is functionally important along the entire gut, specific regional regulatory mechanisms involved in the maintenance of this barrier are poorly defined. Herein, we identified Gata4 as a crucial regulator of barrier integrity in the mouse proximal intestinal epithelium. Conditional deletion of Gata4 in the intestine led to a drastic increase in claudin-2 expression that was associated with an important increase of gut barrier permeability without causing overt spontaneous inflammation. Administration of indomethacin, a non-steroidal anti-inflammatory drug (NSAID) that causes enteritis, led to rapid and restricted proximal small intestinal injuries in Gata4 mutant mice as opposed to control mice. Comparative analysis of gene transcript profiles from indomethacin-challenged control and Gata4 mutant mice identified defects in epithelial cell survival, inflammatory cell recruitment and tissue repair mechanisms. Altogether, these observations identify Gata4 as a novel crucial regulator of the intestinal epithelial barrier and as a critical epithelial transcription factor implicated in the maintenance of proximal intestinal mucosal integrity after injury.

show abstract

Epithelial Tyrosine Phosphatase SHP-2 Protects against Intestinal Inflammation in Mice

Cited by 37 publications

References 57 publications

Loss of SHP-2 activity in CD4+ T cells promotes melanoma progression and metastasis

Loss of SHP-2 activity in CD4+ T cells promotes melanoma progression and metastasis

SH2 Domain-Containing Protein Tyrosine Phosphatase 2 and Focal Adhesion Kinase Protein Interactions Regulate Pulmonary Endothelium Barrier Function

Gata4 is critical to maintain gut barrier function and mucosal integrity following epithelial injury

Contact Info

Product

Resources

About