Gs Protein-coupled Receptor Agonists Induce Transactivation of the Epidermal Growth Factor Receptor in T84 Cells

Bertelsen, Lone S.; Barrett, Kim E.; Keely, Stephen J.

doi:10.1074/jbc.m311612200

Cited by 54 publications

(38 citation statements)

References 59 publications

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“…The A 1 -mediated chloride current induced by luminal adenosine might involve a similar mechanism because in airway epithelial cells, A 1 agonists activate chloride secretion via mobilization of intracellular calcium (35). Other mechanisms also deserve consideration in light of the recent elegant studies of the group of Barrett and colleagues (2,19), who established that transactivation of the EGF receptor (EGFR) is a new mechanism controlling intestinal chloride secretion with downstream effectors involving either phosphatidylinositol 3-kinase (PI3-kinase) or MAPK. For instance, the full chloride secretory response to VIP in T84 monolayers involves activation of PI3-kinase through EFGR transactivation by a typical G scoupled receptor (2).…”

Section: Discussionmentioning

confidence: 99%

Luminal adenosine stimulates chloride secretion through A₁receptor in mouse jejunum

Ghanem¹,

Lövdahl²,

Daré³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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sine is known to stimulate chloride secretion by mouse jejunum. Whereas the receptor on the basolateral side is believed to be A2B, the receptor involved in the luminal effect of adenosine has not been identified. We found that jejuna expressed mRNA for all adenosine receptor subtypes. In this study, we investigated the stimulation of chloride secretion by adenosine in jejuna derived from mice lacking the adenosine receptors of A1 (A1R) and A2A (A2AR) or control littermates. The jejunal epithelium was mounted in a Ussing chamber, and a new method on the basis of impedance analysis was used to calculate the short-circuit current (I sc) values. Chloride secretion was assessed by the I sc after inhibition of the sodium-glucose cotransporter by adding phloridzin to the apical bathing solution. The effect of apical adenosine on chloride secretion was lost in jejuna from mice lacking the A 1R. There was no difference in the response to basolaterally applied adenosine or to apical forskolin. Furthermore, in jejuna from control mice, the effect of apical adenosine was also abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine, a specific A 1R antagonist. Responses to adenosine were identical in jejuna from control and A 2AR knockout mice. This study demonstrates that A1R (and not A 2AR) mediates the enhancement of chloride secretion induced by luminal adenosine in mice jejunum. intestinal secretion; diarrhea; chloride channels ADENOSINE IS AN ENDOGENOUS nucleoside that can regulate a large number of physiological and pathophysiological processes (4, 9 -16, 18, 24, 25, 31). Adenosine is generated by hydrolysis of intra-or extracellular adenine nucleotides (11).

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Section: Discussionmentioning

confidence: 99%

Luminal adenosine stimulates chloride secretion through A₁receptor in mouse jejunum

Ghanem¹,

Lövdahl²,

Daré³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…At this time there is no implication of the involvement of other G proteins in NT signaling in NCM460 cells. Because G proteins including G s (45), G i (28, 40), G q/11 (46,47), and G 13 (48) have been shown to mediate transactivation of the EGF receptor, further studies are needed to identify which G protein(s) mediates EGF receptor transactivation and to determine the signaling molecules involved in this NT response.…”

Section: Discussionmentioning

confidence: 99%

Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells

Zhao¹,

Zhan²,

Koon³

et al. 2004

Journal of Biological Chemistry

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Expression of the neuropeptide neurotensin (NT) and its high affinity receptor (NTR1) is increased during the course of Clostridium difficile toxin A-induced acute colitis, and NTR1 antagonism attenuates the severity of toxin A-induced inflammation. We recently demonstrated in non-transformed human colonic epithelial NCM460 cells that NT treatment caused activation of a Ras-mediated MAP kinase pathway that significantly contributes to NT-induced interleukin-8 (IL-8) secretion. Here we used NCM460 cells, which normally express low levels of NTR1, and NCM460 cells stably transfected with NTR1 to identify the upstream signaling molecules involved in NT-NTR1-mediated MAP kinase activation. We found that inhibition of the epidermal growth factor receptor (EGFR) by either an EGFR neutralizing antibody or by its specific inhibitor AG1478 (0.2 M) blocked NT-induced MAP kinase activation. Moreover, NT stimulated tyrosine phosphorylation of the EGFR, and pretreatment with a broad spectrum metalloproteinase inhibitor batimastat reduced NT-induced MAP kinase activation. Using neutralizing antibodies against the EGFR ligands EGF, heparin-binding-EGF, transforming growth factor-␣ (TGF␣), or amphiregulin we have shown that only the anti-TGF␣ antibody significantly decreases NT-induced phosphorylation of EGFR and MAP kinases. Furthermore, inhibition of the EGF receptor by AG1478 significantly reduced NT-induced IL-8 promoter activity and IL-8 secretion. This is the first report demonstrating that NT binding to NTR1 transactivates the EGFR and that this response is linked to NT-mediated proinflammatory signaling. Our findings indicate that matrix metalloproteinase-mediated release of TGF␣ and subsequent EGFR transactivation triggers a NT-mediated MAP kinase pathway that leads to IL-8 gene expression in human colonic epithelial cells.Neurotensin (NT), 1 a 13-amino acid neuropeptide originally isolated by Carraway and Leeman (1) from bovine hypothalamus, is also localized in the gastrointestinal tract (2). In the small intestine NT is synthesized and secreted by specific mucosal endocrine cells in response to several different stimuli (3, 4). NT alters motility in the stomach, small bowel, and colon (5-7), stimulates secretion in the ileum (8), pancreas (9), and the biliary tract (10), and causes Cl Ϫ secretion from human colonic mucosa (11). NT also stimulates growth and regeneration of the intestinal mucosa (12, 13) and has been implicated in the pathophysiology of colon cancer (14, 15).Two G protein-coupled receptors (GPCRs) have been described for NT, a high affinity (NTR1) and a low affinity (NTR2) receptor (16). A third, non-G protein-coupled receptor has also been identified (17). Several studies underline the importance of NTR1 in several intestinal pathologic conditions. For example, administration of the specific NTR1 antagonist SR 48692 to rats inhibits colonic mucin and prostaglandin E2 secretion and mast cell activation in response to immobilization stress (18). NTR1 antagonism also reduces colonic secretion and infla...

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“…Several studies have shown that transactivation of the epidermal growth factor receptor (EGFR) reduces the extent of G q -protein coupled receptor induced Cl -secretion while increasing secretory responses mediated by G s -protein coupled receptors in colonic epithelial cells [24,25]. Recent evidence has also suggested EGFR can be transactivated by steroid hormones in a nongenomic fashion [26][27][28][29].…”

Section: Signaling Pathways Involved In the Antisecretory Response Tomentioning

confidence: 99%

Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon

2011

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Gs Protein-coupled Receptor Agonists Induce Transactivation of the Epidermal Growth Factor Receptor in T84 Cells

Cited by 54 publications

References 59 publications

Luminal adenosine stimulates chloride secretion through A₁receptor in mouse jejunum

Luminal adenosine stimulates chloride secretion through A₁receptor in mouse jejunum

Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells

Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon

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Gs Protein-coupled Receptor Agonists Induce Transactivation of the Epidermal Growth Factor Receptor in T84 Cells

Cited by 54 publications

References 59 publications

Luminal adenosine stimulates chloride secretion through A1receptor in mouse jejunum

Luminal adenosine stimulates chloride secretion through A1receptor in mouse jejunum

Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells

Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon

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Luminal adenosine stimulates chloride secretion through A₁receptor in mouse jejunum

Luminal adenosine stimulates chloride secretion through A₁receptor in mouse jejunum