Trypsin activates pancreatic duct epithelial cell ion channels through proteinase-activated receptor-2

Nguyen, Toan D.; Moody, Mark W.; Steinhoff, Martin; Okolo, Charles; Koh, Duk Su; Bunnett, Nigel W.

doi:10.1172/jci2539

Cited by 168 publications

(152 citation statements)

References 34 publications

Supporting

Mentioning

141

Contrasting

Order By: Relevance

“…These concentrations are much lower than the concentrations of trypsin required for hydrolysis of proteins in the duodenal lumen (Green and Nasset, 1980). Further, they are lower than the concentrations of trypsin required to trigger PAR-2-mediated regulation of short-term events such as prostaglandin secretion in small intestine enterocytes (Kong et al, 1997) or net electrogenic ion transport in pancreatic duct epithelial cells (Nguyen et al, 1999) that are in the micromolar range. This suggests that colonic cancer cells may have an exquisite sensitivity to trypsin.…”

Section: Discussionmentioning

confidence: 94%

“…The presence of PAR-2 has been revealed in a variety of tissues (Nystedt et al, 1994;D'Andrea et al, 1998); in particular high expression has been observed in the gastrointestinal tract (Nystedt Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2 Bohm et al, 1996b;Kong et al, 1997;D'Andrea et al, 1998;Nguyen et al, 1999). These receptors are functional since activation of PAR-2 by trypsin or AP2 induces ion secretion and prostaglandin production in normal intestine (Kong et al, 1997;Vergnolle et al, 1998).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

et al. 2001

View full text Add to dashboard Cite

SummaryThe protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved and activated by trypsin. We investigated the expression of PAR-2 and the role of trypsin in cell proliferation in human colon cancer cell lines. A total of 10 cell lines were tested for expression of PAR-2 mRNA by Northern blot and RT-PCR. PAR-2 protein was detected by immunofluorescence. Trypsin and the peptide agonist SLIGKV (AP2) were tested for their ability to induce calcium mobilization and to promote cell proliferation on serum-deprived cells. PAR-2 mRNA was detected by Northern blot analysis in 6 out of 10 cell lines Cl.19A, SW480,. Other cell lines expressed low levels of transcripts, which were detected only by RT-PCR. Further results were obtained with HT-29 cells: (1) PAR-2 protein is expressed at the cell surface; (2) an increase in intracellular calcium concentration was observed upon trypsin (1-100 nM) or AP2 (10-100 µM) challenges; (3) cells grown in serum-deprived media supplemented with trypsin (0.1-1 nM) or AP2 (1-300 µM) exhibited important mitogenic responses (3-fold increase of cell number). Proliferative effects of trypsin or AP2 were also observed in other cell lines expressing PAR-2. These data show that subnanomolar concentrations of trypsin, acting at PAR-2, promoted the proliferation of human colon cancer cells. The results of this study indicate that trypsin could be considered as a growth factor and unravel a new mechanism whereby serine proteases control colon tumours.

show abstract

Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

et al. 2001

View full text Add to dashboard Cite

show abstract

“…Proteinase-activated receptors (PARs) are G-protein coupled receptors (Nguyen et al, 1999). PAR2 (F2RL1) is one of the four known PARs and has been shown to play a role in secretion, smooth muscle contractility, neuromodulation, inflammation, fibrosis, angiogenesis and cancer metastasis (Bertog et al, 1999;Cocks et al, 1999;Danahay et al, 2001;Fiorucci et al, 2001;Hoogerwerf et al, 2001;Richard et al, 2001;Vergnolle et al, 2001;Frungieri et al, 2002;Hollenberg, 2002;Milia et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Identification of novel VHL targets that are associated with the development of renal cell carcinoma

et al. 2006

View full text Add to dashboard Cite

von Hippel-Lindau (VHL) disease is a dominantly inherited family cancer syndrome characterized by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma (RCC) and phaeochromocytoma. Specific germline VHL mutations may predispose to haemangioblastomas, RCC and phaeochromocytoma to a varying extent. Although dysregulation of the hypoxia-inducible transcription factor-2 and JunB have been linked to the development of RCC and phaeochromocytoma, respectively, the precise basis for genotype-phenotype correlations in VHL disease have not been defined. To gain insights into the pathogenesis of RCC in VHL disease we compared gene expression microarray profiles in a RCC cell line expressing a Type 1 or Type 2B mutant pVHL (RCC-associated) to those of a Type 2A or 2C mutant (not associated with RCC). We identified 19 differentially expressed novel VHL target genes linked to RCC development. Eight targets were studied in detail by quantitative real-time polymerase chain reaction (three downregulated and five upregulated by wild-type VHL) and for six genes the effect of VHL inactivation was mimicked by hypoxia (but hypoxicinduction of smooth muscle alpha-actin 2 was specific for a RCC cell line). The potential role of four RCCassociated VHL target genes was assessed in vitro. NB thymosin beta (TMSNB) and proteinase-activated receptor 2 (PAR2) (both downregulated by wt pVHL) increased cell growth and motility in a RCC cell line, but aldehyde dehydrogenase (ALDH)1 and ALDH7 had no effect. These findings implicate TMSNB and PAR2 candidate oncogenes in the pathogenesis of VHL-associated RCC.

show abstract

“…Pancreas -In the pancreas, PAR-2 is expressed on both acinar cells and duct epithelium (Nguyen et al 1999), where its activation stimulates amylase secretion and electrolyte transport, respectively. Some forms of pancreatitis are characterized by premature activation of trypsinogen to trypsin, which activates PAR-2, suggesting that PAR-2 may play a role in pancreatic inflammation.…”

Section: Effect Of Pars On Epithelial Functionmentioning

confidence: 99%

Epithelial effects of proteinase-activated receptors in the gastrointestinal tract

MacNaughton

2005

Mem. Inst. Oswaldo Cruz

View full text Add to dashboard Cite

Trypsin activates pancreatic duct epithelial cell ion channels through proteinase-activated receptor-2

Cited by 168 publications

References 34 publications

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

Identification of novel VHL targets that are associated with the development of renal cell carcinoma

Epithelial effects of proteinase-activated receptors in the gastrointestinal tract

Contact Info

Product

Resources

About