6 TUMOR NECROSIS FACTOR ALPHA REGULATES TYROSINE PHOSPHORYLATION AND EXPRESSION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR IN INTESTINAL EPITHELIAL CELLS

ABSTRACT The kinase TAK1, a mitogen-activated protein kinase kinase kinase (MAP3K), has been widely accepted as a key kinase activating NF-κB and MAPKs in tumor necrosis factor alpha (TNF-α) signaling. We have recently reported that TAK1 regulates the transient phosphorylation and endocytosis of epidermal growth factor receptor (EGFR) in a tyrosine kinase activity-independent manner. In the present study, we found that Thr-669 in the juxtamembrane domain and Ser-1046/1047 in the carboxyl-terminal regulatory domain were transiently phosphorylated in response to TNF-α. Experiments using chemical inhibitors and small interfering RNA demonstrated that TNF-α-mediated phosphorylation of Thr-669 and Ser-1046/7 were differently regulated via TAK1-extracellular signal-regulated kinase (ERK) and TAK1-p38 pathways, respectively. In addition, p38, but not ERK, was involved in the endocytosis of EGFR. Surprisingly, modified EGFR was essential to prevent apoptotic cellular responses; however, the EGFR pathway was independent of the NF-κB antiapoptotic pathway. These results demonstrated that TAK1 controls two different signaling pathways, IκB kinase-NF-κB and MAPK-EGFR, leading to the survival of cells exposed to the death signal from the TNF-α receptor.

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Rotavirus infection induces increased chloride secretion, altered barrier function and epidermal growth factor receptor (EGF-R) polyubiquitination in intestinal epithelial cells (IEC)

Gastroenterology ◽

10.1016/s0016-5085(01)83508-3 ◽

2001 ◽

Vol 120 (5) ◽

pp. A704-A705

Author(s):

S RESTALENERT ◽

K BARRETT

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Epithelial Cells ◽

Barrier Function ◽

Intestinal Epithelial Cells ◽

Growth Factor Receptor ◽

Chloride Secretion ◽

Intestinal Epithelial ◽

Epidermal Growth

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00358.2011 ◽

2012 ◽

Vol 303 (1) ◽

pp. G111-G119 ◽

Cited By ~ 17

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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