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Gαq and Gβγ regulate PAR-1 signaling of thrombin-induced NF-κB activation and ICAM-1 transcription in endothelial cells
Rahman A.; True A.L.; Anwar K.N.; Ye R.D.; Voyno-Yasenetskaya T.A.; Malik A.B.
2002-09-06
Source PublicationCirculation Research
ISSN00097330
Volume91Issue:5Pages:398-405
AbstractAs thrombin binding to the G protein-coupled proteinase activated receptor-1 (PAR-1) induces endothelial adhesivity to leukocytes through NF-κB activation and intercellular adhesion molecule-1 (ICAM-1) expression, we determined the signaling pathways mediating the response. Studies showed that the heterotrimeric G proteins, Gα, and the GΒγ dimer were key determinants of the PAR-1 agonist peptide (TFLLRNPNDK)-induced NF-κB activation and ICAM-1 expression in endothelial cells. Cotransfection of RGS3T, a regulator of G-protein signaling that inhibits Gα or α-transducin (Gα), a scavenger of the GΒγ, markedly decreased NF-κB activity induced by PAR-1 activation. We determined the downstream signaling targets activated by Gα and GΒγ that mediate NF-κB activation. Expression of the kinase-defective protein kinase C (PKC)-δ mutant inhibited NF-κB activation induced by the constitutively active Gα mutant, but had no effect on NF-κB activity induced by GΒγ. In related experiments, NF-κB as well as ICAM-1 promoter activation induced by GΒγ were inhibited by the expression of the dominant-negative mutant of 85-kDa regulatory subunit of PI 3-kinase; however, the expression of this mutant had no effect on the response induced by activated Gα. Cotransfection of the catalytically inactive Akt mutant inhibited the NF-κB activation induced by the constitutively active PI 3-kinase mutant as well as that by the activated forms of Gα and PKC-δ. These results support a model in which ligation of PAR-1 induces NF-κB activation and ICAM-1 transcription by the engagement of parallel Gα/PKC-δ and GΒγ/PI3-kinase pathways that converge at Akt.
KeywordAkt G proteins Intercellular adhesion molecule-1 Nuclear factor-κB Protein kinase C-δ
DOI10.1161/01.RES.0000033520.95242.A2
URLView the original
Language英語
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Cited Times [WOS]:111   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
AffiliationUniversity of Illinois College of Medicine
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Rahman A.,True A.L.,Anwar K.N.,et al. Gαq and Gβγ regulate PAR-1 signaling of thrombin-induced NF-κB activation and ICAM-1 transcription in endothelial cells[J]. Circulation Research,2002,91(5):398-405.
APA Rahman A.,True A.L.,Anwar K.N.,Ye R.D.,Voyno-Yasenetskaya T.A.,&Malik A.B..(2002).Gαq and Gβγ regulate PAR-1 signaling of thrombin-induced NF-κB activation and ICAM-1 transcription in endothelial cells.Circulation Research,91(5),398-405.
MLA Rahman A.,et al."Gαq and Gβγ regulate PAR-1 signaling of thrombin-induced NF-κB activation and ICAM-1 transcription in endothelial cells".Circulation Research 91.5(2002):398-405.
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