scholarly journals Consequences of DirectVersusIndirect Activation of Epidermal Growth Factor Receptor in Intestinal Epithelial Cells Are Dictated by Protein-tyrosine Phosphatase 1B

2007 ◽  
Vol 282 (18) ◽  
pp. 13303-13315 ◽  
Author(s):  
Declan F. McCole ◽  
Anh Truong ◽  
Michael Bunz ◽  
Kim E. Barrett
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Protein Tyrosine Phosphatase ◽  
Intestinal Epithelial Cells ◽  
Tyrosine Phosphatase ◽  
Growth Factor Receptor ◽  
Protein Tyrosine Phosphatase 1B ◽  
Intestinal Epithelial ◽  
Epidermal Growth

Epidermal growth factor receptor transactivation is required for proteinase-activated receptor-2-induced COX-2 expression in intestinal epithelial cells

2012 ◽  
Vol 303 (1) ◽  
pp. G111-G119 ◽  
Author(s):  
Christina L. Hirota ◽  
France Moreau ◽  
Vadim Iablokov ◽  
Michael Dicay ◽  
Bernard Renaux ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Intestinal Epithelial Cells ◽  
Growth Factor Receptor ◽  
Intestinal Epithelial ◽  
Kinase Signaling ◽  
Epidermal Growth ◽  
Cox 2

Proteinase-activated receptor (PAR)2, a G protein-coupled receptor activated by serine proteinases, has been implicated in both intestinal inflammation and epithelial proliferation. Cyclooxygenase (COX)-2 is overexpressed in the gut during inflammation as well as in colon cancer. We hypothesized that PAR2 drives COX-2 expression in intestinal epithelial cells. Treatment of Caco-2 colon cancer cells with the PAR2-activating peptide 2-furoyl-LIGRLO-NH2 (2fLI), but not by its reverse-sequence PAR2-inactive peptide, for 3 h led to an increase in intracellular COX-2 protein expression accompanied by a COX-2-dependent increase in prostaglandin E2 production. 2fLI treatment for 30 min significantly increased metalloproteinase activity in the culture supernatant. Increased epidermal growth factor receptor (EGFR) phosphorylation was observed in cell lysates following 40 min of treatment with 2fLI. The broad-spectrum metalloproteinase inhibitor marimastat inhibited both COX-2 expression and EGFR phosphorylation. The EGFR tyrosine kinase inhibitor PD153035 also abolished 2fLI-induced COX-2 expression. Although PAR2 activation increased ERK MAPK phosphorylation, neither ERK pathway inhibitors nor a p38 MAPK inhibitor affected 2fLI-induced COX-2 expression. However, inhibition of either Src tyrosine kinase signaling by PP2, Rho kinase signaling by Y27632, or phosphatidylinositol 3 (PI3) kinase signaling by LY294002 prevented 2fLI-induced COX-2 expression. Trypsin increased COX-2 expression through PAR2 in Caco-2 cells and in an EGFR-dependent manner in the noncancerous intestinal epithelial cell-6 cell line. In conclusion, PAR2 activation drives COX-2 expression in Caco-2 cells via metalloproteinase-dependent EGFR transactivation and activation of Src, Rho, and PI3 kinase signaling. Our findings provide a mechanism whereby PAR2 can participate in the progression from chronic inflammation to cancer in the intestine.

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