کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10815843 | 1058506 | 2010 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Proteinase-activated receptor-2 mediated inhibition of TNFα-stimulated JNK activation - A novel paradigm for Gq/11 linked GPCRs
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کلمات کلیدی
IL-6GF109203XNHEKTRADDTRAFMADDphorbol 12-myristate 13-acetateFADDPAR-2PKCGPCRTNFαJnkc-Jun N-terminal protein kinase - C-Jun N-terminal protein kinaseG-protein-coupled receptors - G-پروتئین گیرندهPMA - LDC هاNFκB - NFKBinterleukin-6 - اینترلوکین ۶Fas-associated death domain - حوزه مرگ مرتبط Fasnuclear factor kappa B - فاکتور هسته ای کاپا BRIP - پاره کردنProtein kinase C - پروتئین کیناز سیmitogen-activated protein kinase - پروتئین کیناز فعال با mitogenReceptor interacting protein - پروتئین گیرنده گیرندهproteinase-activated receptor-2 - پروتئیناز فعال گیرنده-2MAP kinase - کیناز MAPproteinase-activated receptor 2 - گیرنده پروتئیناز فعال 2
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
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چکیده انگلیسی
In this study we examined the potential for PAR2 and TNFα to synergise at the level of MAP kinase signalling in PAR2 expressing NCTC2544 cells. However, to our surprise we found that activation of PAR2 by trypsin or the specific activating peptide SLIGKV-OH strongly inhibited both the phosphorylation and activity of JNK. In contrast neither p38 MAP kinase nor ERK activation was affected although TNFα stimulated IκBα loss was partially reversed. The inhibitory effect was not observed in parental cells nor in cells expressing PAR4, however inhibition was reversed by pre-incubation with the novel PAR2 antagonist K14585, suggesting that the effect is specific for PAR2 activation. SLIGKV-OH was found to be more potent in inhibiting TNFα-induced JNK activation than in stimulating JNK alone, suggesting agonist-directed signalling. The PKC activator PMA, also mimicked the inhibitory effect of SLIGKV-OH, and the effects of both agents were reversed by pre-treatment with the PKC inhibitor, GF109203X. Furthermore, incubation with the novel Gq/11 inhibitor YM25480 also reversed PAR2 mediated inhibition. Activation of PAR2 was found to disrupt TNFR1 binding to RIP and TRADD and this was reversed by both GF109203X and YM25480. A similar mode of inhibition observed in HUVECs through PAR2 or P2Y2 receptors demonstrates the potential of a novel paradigm for GPCRs linked to Gq/11, in mediating inhibition of TNFα-stimulated JNK activation. This has important implications in assessing the role of GPCRs in inflammation and other conditions.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 22, Issue 2, February 2010, Pages 265-273
Journal: Cellular Signalling - Volume 22, Issue 2, February 2010, Pages 265-273
نویسندگان
Kathryn McIntosh, Margaret R. Cunningham, Laurence Cadalbert, John Lockhart, Gary Boyd, W.R. Ferrell, Robin Plevin,