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Xiaochen Liu, Bin Zhang, Jian-Xing Ma; SERPINA4, an Angiogenic Inhibitor Expressed in the Human Retina, Binds to LRP6 to Inhibit Canonical Wnt Signaling. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3574.
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We have previously shown that the canonical Wnt signaling pathway is activated in diabetic retinopathy. SERPINA4, a member of the serine proteinase inhibitor superfamily, has been shown to have anti-angiogenic activity, and its levels have been found to be decreased in the vitreous in patients with diabetic retinopathy. The purpose of this study was to determine whether SERPINA4 can modulate Wnt signaling and its mechanism of action.
Co-immunoprecipitation of the extracellular domain of LRP6, a Wnt co-receptor, with SERPINA4 was performed. The Wnt effector, TCF/beta-catenin transcriptional activity was measured by luciferase assay (TOPFLASH). An ELISA-based binding assay was used to determine the binding of SERPINA4 with LRP6 and potential competition between SERPINA4 and Wnt3a for binding to LRP6.
SERPINA4 was pulled down by LRP6 from human serum-derived SERPINA4 and conditioned medium containing recombinant SERPINA4. SERPINA4 decreased the Wnt3a-induced TOPFLASH activity in a concentration-dependent manner. In binding assays, SERPINA4 showed a concentration-dependent and saturable binding with the extracellular domain of LRP6. Furthermore, SERPINA4 competed with Wnt3a for binding to the extracellular domain of LRP6.
SERPINA4 functions as an inhibitor of Wnt signaling through binding to LRP6. This may represent a molecular mechanism for its anti-angiogenic activity. SERPINA4 may have therapeutic potential for the treatment of diabetic retinopathy.
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