Lee, Lawrence K and Bryant, Katherine J and Bouveret, Romaric and Lei, Pei-Wen and Duff, Anthony P and Harrop, Stephen J and Huang, Edwin P and Harvey, Richard P and Gelb, Michael H and Gray, Peter P and Curmi, Paul M and Cunningham, Anne M and Church, W Bret and Scott, Kieran F (2013) Selective inhibition of human group IIA-secreted phospholipase A2 (hGIIA) signaling reveals arachidonic acid metabolism is associated with colocalization of hGIIA to vimentin in rheumatoid synoviocytes. The Journal of Biological Chemistry, 288 (21). pp.15269-79. ISSN 1083-351X (PMC OA)
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Abstract
Human group IIA secreted phospholipase A2 (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.
(NHMRC grants (numbers not listed), The Rebecca Cooper Foundation, the Cancer Council NSW, and the Prostate Cancer Foundation).
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 06 Jan 2016 23:18 |
| Last Modified: | 18 Mar 2016 00:38 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/125 |
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