Protease activated receptors: theme and variations

O’Brien, Peter J.; Molino, Marina; Kahn, Mark L.; Brass, Lawrence F.

doi:10.1038/sj.onc.1204194

Cited by 209 publications

(237 citation statements)

References 111 publications

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“…Since the initial characterization of PAR-2 and its activation by trypsin, other activating serine proteases have been reported. These include tryptase, the membrane-type serine proteasel, the tissue factor VIIa Xa complex (see O'Brien et al, 2001 for a review), a proteinase isolated from Porphyromonas gingivalis (Vergnolle, 2000) and acrosin (Smith et al, 2000). Among all these serine proteases, only tryptase and the tissue factor VIIa Xa complex might reasonably be expected to be present within the colonic cancer environment.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2001

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2001

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“…PAR contributions can differ among cells and species (4,44), but our experiments on ␥-thrombin, PPACK, and the induction kinetics ruled out an involvement. Similarly, testing a panel of PAR agonists, i.e.…”

Section: Thrombin As An Assumed Activator Of Microglial Releasementioning

confidence: 99%

The Microglia-activating Potential of Thrombin

Hanisch

Rossum

Xie

et al. 2004

Journal of Biological Chemistry

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The serine protease thrombin is known as a blood coagulation factor. Through limited cleavage of proteinase-activated receptors it can also control growth and functions in various cell types, including neurons, astrocytes, and microglia (brain macrophages). A number of previous studies indicated that thrombin induces the release of proinflammatory cytokines and chemokines from microglial cells, suggesting another important role for the protease beyond hemostasis. In the present report, we provide evidence that this effect is not mediated by any proteolytic or non-proteolytic mechanism involving thrombin proper. Inhibition of the enzymatic thrombin activity did not affect the microglial release response. Instead the cyto-/chemokine-inducing activity solely resided in a high molecular weight protein fraction that could be isolated in trace amounts even from apparently homogenous ␣-and ␥-thrombin preparations. High molecular weight material contained thrombin-derived peptides as revealed by mass spectrometry but was devoid of thrombin-like enzymatic activity. Separated from the high molecular weight fraction by fast protein liquid chromatography, enzymatically intact ␣-and ␥-thrombin failed to trigger any release. Our findings may force a revision of the notion that thrombin itself is a direct proinflammatory release signal for microglia. In addition, they could be relevant for the study of other cellular activities and their assignment to this protease.

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“…It is a G protein-coupled receptor activated with proteolytic cleavage of the extracellular domain (55). Thrombin cleaves PAR-1, PAR-3, and PAR-4, while PAR-2 is preferentially cleaved by trypsin and tryptase (55,56) and cleaves, to a lesser extent, PAR-1 (54). Interestingly, mRNA for PAR-3 was recently found to be expressed by eosinophils (14).…”

Section: Discussionmentioning

confidence: 99%

Tryptase Activates the Mitogen-Activated Protein Kinase/Activator Protein-1 Pathway in Human Peripheral Blood Eosinophils, Causing Cytokine Production and Release

Temkin¹,

Kantor²,

Weg³

et al. 2002

The Journal of Immunology

114

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We have previously shown that mast cells enhance eosinophil survival and activation. In this study we further characterized mast cell activity toward eosinophils. Sonicate of both rat peritoneal mast cells and the human mast cell line 1 (HMC-1) induced a concentration-dependent IL-6 and IL-8 release from human peripheral blood eosinophils (ELISA). HMC-1-induced IL-8 release was significantly reduced by the tryptase inhibitors GW-45 and GW-58 (90 and 87%, respectively, at an optimal concentration) but not by anti-stem cell factor, anti-TNF-α, or anti-IFN-γ neutralizing Abs or by the antihistamine drugs pyrilamine and cimetidine. In a manner similar to HMC-1, human recombinant tryptase induced the expression of mRNA for IL-8 (RT-PCR) and caused IL-8 release from the eosinophils. Addition of cycloheximide, actinomycin D, dexamethasone, PD 98059, curcumin, or SB 202190 completely inhibited the tryptase-induced IL-6 and IL-8 release. In contrast, cyclosporin A had no effect on tryptase-induced IL-8 release. Tryptase caused phosphorylation of extracellular signal-regulated kinases 1 and 2, c-Jun N-terminal kinases 1 and 2, and p38 (Western blot). Tryptase also induced the translocation of c-Jun from the cytosol to the nucleus (confocal microscopy) and enhanced AP-1 binding activity to the DNA (EMSA). Eosinophils were found to express proteinase-activated receptor 2 (FACS). When eosinophils were incubated with tryptase in the presence of anti-proteinase-activated receptor 2 antagonist Abs a significant decrease in the IL-6 and IL-8 release occurred. In summary, we have demonstrated that the preformed mast cell mediator tryptase induces cytokine production and release in human peripheral blood eosinophils by the mitogen-activated protein kinase/AP-1 pathway.

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Protease activated receptors: theme and variations

Cited by 209 publications

References 111 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

The Microglia-activating Potential of Thrombin

Tryptase Activates the Mitogen-Activated Protein Kinase/Activator Protein-1 Pathway in Human Peripheral Blood Eosinophils, Causing Cytokine Production and Release

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