Identification of a novel inhibitor of the canonical Wnt pathway.

Wnt signaling is known to regulate multiple processes including angiogenesis, inflammation, and fibrosis. Here, we identified a novel inhibitor of the Wnt pathway, pigment epithelium-derived factor (PEDF), a multifunctional serine proteinase inhibitor. Both overexpression of PEDF in transgenic mice and administration of PEDF protein attenuated Wnt signaling induced by retinal ...
ischemia. Furthermore, PEDF knockdown by small interfering RNA (siRNA) and PEDF knockout in PEDF(-/-) mice induced activation of Wnt signaling. PEDF bound to LRP6, a Wnt coreceptor, with high affinity (K(d) [dissociation constant] of 3.7 nM) and blocked the Wnt signaling induced by Wnt ligand. The physical interaction of PEDF with LRP6 was confirmed by a coprecipitation assay, which showed that PEDF bound to LRP6 at the E1E2 domain. In addition, binding of PEDF to LRP6 blocked Wnt ligand-induced LRP6-Frizzled receptor dimerization, an essential step in Wnt signaling. These results suggest that PEDF is an endogenous antagonist of LRP6, and blocking Wnt signaling may represent a novel mechanism for its protective effects against diabetic retinopathy.
Mesh Terms:
Animals, Cell Line, Diabetic Retinopathy, Eye Proteins, Humans, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-6, Mice, Mice, Knockout, Mice, Transgenic, Nerve Growth Factors, Oxygen, RNA, Small Interfering, Receptors, LDL, Retina, Serine Proteinase Inhibitors, Serpins, Signal Transduction, Wnt Proteins, beta Catenin
Mol. Cell. Biol.
Date: Jul. 01, 2011
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