title: Identification of a novel inhibitor of the canonical Wnt pathway.
abstract: 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.
authors.affiliation: Department of Physiology, Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, usa.
authors.forename: Kyoungmin
authors.initials: K
authors.lastname: Park
authors.forename: Kyungwon
authors.initials: K
authors.lastname: Lee
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Ti
authors.initials: T
authors.lastname: Zhou
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.forename: Guoquan
authors.initials: G
authors.lastname: Gao
authors.forename: Anne R
authors.initials: AR
authors.lastname: Murray
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
mesh_terms: D000818:Animals; D002460:Cell Line; D003930:Diabetic Retinopathy / Q000503:physiopathology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000633:toxicity; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D026502:LDL-Receptor Related Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D009414:Nerve Growth Factors; D010100:Oxygen; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D051153:Wnt Proteins; D051176:beta Catenin; D000099174:Pigment Epithelium-Derived Factor; C555475:LRP6 protein, human; C555476:Lrp6 protein, mouse; C036053:VLDL receptor