G-protein-dependent and -independent pathways regulate proteinase-activated receptor-2 mediated p65 NFkappaB serine 536 phosphorylation in human keratinocytes

Cellular Signalling
Fui Goon GohRobin Plevin

Abstract

The mechanisms underpinning the coupling of GPCRs, such as PAR-2, to the phosphorylation of p65 NFkappaB have not been investigated. In the current study we found that trypsin and the selective PAR-2 activating peptide, 2f-LIGKV-OH, stimulated large and sustained increases in the serine 536 phosphorylation of p65/RelA in a transfected skin epithelial cell line and primary keratinocytes. Parallel experiments showed that in both cell types, p65 NFkappaB phosphorylation is mediated through the selective activation of IKK2. Treatment with PKC inhibitor GF109203X or PKCalpha siRNA reduced phosphorylation at 15 min but not 30 min, whilst rottlerin, a selective PKCdelta inhibitor and PKCdelta siRNA reduced the response at both time points. Pre-treatment of cells with the novel Gq/11 inhibitor YM-254890 and Gq/11 siRNA caused a similar pattern of inhibition and also reduced PAR-2-mediated NFkappaB transcriptional activity. Furthermore, stimulation of cells through a novel PAR-2 mutant PAR-2(34-43), delayed p65 phosphorylation but was without effect on the kinetics of ERK activation. Inhibition of Gi or G12/13 pathways by pertussis toxin pre-treatment or over-expression of the RGS mutant Lsc, also did not effect NFkappaB phosphorylation...Continue Reading

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Citations

Oct 11, 2011·Rheumatology·Fui G Goh, Kim S Midwood
Feb 1, 2011·Pharmacology & Therapeutics·Mark N AdamsJohn D Hooper
Jun 16, 2015·American Journal of Respiratory Cell and Molecular Biology·Tetsuya HommaRobert P Schleimer
Oct 17, 2013·Scientific Reports·Masanori NakayamaTakeshi Miyamoto
Aug 4, 2011·Journal of Thrombosis and Haemostasis : JTH·W RufF Schaffner
May 10, 2018·The Journal of Experimental Medicine·Ying DuHuaxi Xu
Jun 30, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Hideaki KouzakiHirohito Kita

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