Selective inhibition of human group IIA-secreted phospholipase A(2) (hGIIA) signaling reveals arachidonic acid metabolism Is associated with colocalization of hGIIA to vimentin in rheumatoid synoviocytes

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dc.contributor.authorLee, LKen_AU
dc.contributor.authorBryant, KJen_AU
dc.contributor.authorBouveret, Ren_AU
dc.contributor.authorLei, PWen_AU
dc.contributor.authorDuff, APen_AU
dc.contributor.authorHarrop, SJen_AU
dc.contributor.authorHuang, EPen_AU
dc.contributor.authorHarvey, RPen_AU
dc.contributor.authorGelb, MHen_AU
dc.contributor.authorGray, PPen_AU
dc.contributor.authorCurmi, PMGen_AU
dc.contributor.authorCunningham, AMen_AU
dc.contributor.authorChurch, WBen_AU
dc.contributor.authorScott, KFen_AU
dc.date.accessioned2013-10-13T22:54:21Zen_AU
dc.date.available2013-10-13T22:54:21Zen_AU
dc.date.issued2013-05-24en_AU
dc.date.statistics2013-10-14en_AU
dc.description.abstractHuman group IIA secreted phospholipase A(2) (hGIIA) promotes tumor growth and inflammation and can act independently of its well described catalytic lipase activity via an alternative poorly understood signaling pathway. With six chemically diverse inhibitors we show that it is possible to selectively inhibit hGIIA signaling over catalysis, and x-ray crystal structures illustrate that signaling involves a pharmacologically distinct surface to the catalytic site. We demonstrate in rheumatoid fibroblast-like synoviocytes that non-catalytic signaling is associated with rapid internalization of the enzyme and colocalization with vimentin. Trafficking of exogenous hGIIA was monitored with immunofluorescence studies, which revealed that vimentin localization is disrupted by inhibitors of signaling that belong to a rare class of small molecule inhibitors that modulate protein-protein interactions. This study provides structural and pharmacological evidence for an association between vimentin, hGIIA, and arachidonic acid metabolism in synovial inflammation, avenues for selective interrogation of hGIIA signaling, and new strategies for therapeutic hGIIA inhibitor design. © 2013, American Society for Biochemistry and Molecular Biologyen_AU
dc.identifier.citationLee, L. K., Bryant, K. J., Bouveret, R., Lei, P. W., Duff, A. P., Harrop, S. J., Huang, E. P., Harvey, R. P., Gelb, M. H., Gray, P. P., Curmi, P. M., Cunningham, A. M., Church, W. B., & Scott, K. F. (2013). Selective inhibition of human group IIA-secreted phospholipase A(2) (hGIIA) signaling reveals arachidonic acid metabolism Is associated with colocalization of hGIIA to vimentin in rheumatoid synoviocytes. Journal of Biological Chemistry, 288 (21), 15269-15279. doi:10.1074/jbc.M112.397893en_AU
dc.identifier.govdoc5080en_AU
dc.identifier.issn0021-9258en_AU
dc.identifier.issue21en_AU
dc.identifier.journaltitleJournal of Biological Chemistryen_AU
dc.identifier.pagination15269-15279en_AU
dc.identifier.urihttp://dx.doi.org/10.1074/jbc.M112.397893en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/4796en_AU
dc.identifier.volume288en_AU
dc.language.isoenen_AU
dc.publisherAmerical Society Biochemistry Molecular Biology Inc.en_AU
dc.subjectArachidonic aciden_AU
dc.subjectMetabolismen_AU
dc.subjectPharmacologyen_AU
dc.subjectCrystal structureen_AU
dc.subjectRheumatic diseasesen_AU
dc.subjectEnzymesen_AU
dc.titleSelective inhibition of human group IIA-secreted phospholipase A(2) (hGIIA) signaling reveals arachidonic acid metabolism Is associated with colocalization of hGIIA to vimentin in rheumatoid synoviocytesen_AU
dc.typeJournal Articleen_AU
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