Identification of a Novel Inhibitor of the Canonical Wnt Pathway
Identification of a Novel Inhibitor of the Canonical Wnt Pathway
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DOI：
10.1128/mcb.01211-10
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发表时间：
2011-07-01
影响因子：
5.3
通讯作者：
Ma, Jian-xing
中科院分区：
文献类型：
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作者：
Park, Kyoungmin;Lee, Kyungwon;Ma, Jian-xing
已知Wnt信号传导调节多种过程，包括血管生成、炎症和纤维化。在这里，我们确定了一种新的Wnt通路抑制剂，色素上皮衍生因子（PEDF），一种多功能丝氨酸蛋白酶抑制剂。转基因小鼠中PEDF的过表达和PEDF蛋白的施用都减弱了视网膜缺血诱导的Wnt信号传导。此外，通过小干扰RNA（siRNA）和PEDF敲除PEDF-/-小鼠中的PEDF敲除诱导Wnt信号传导的激活。PEDF与Wnt共受体LRP 6以高亲和力结合（K-d [解离常数]为3.7 nM）并阻断Wnt配体诱导的Wnt信号传导。PEDF与LRP 6的物理相互作用通过共沉淀测定来证实，其显示PEDF在E1 E2结构域结合LRP 6。此外，PEDF与LRP 6的结合阻断了Wnt配体诱导的LRP 6-Frizzled受体二聚化，这是Wnt信号传导中的一个重要步骤。这些结果表明，PEDF是LRP 6的内源性拮抗剂，并且阻断Wnt信号传导可能代表其对糖尿病视网膜病变的保护作用的新机制。
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.