Pan Weijun, Choi Sun-Cheol, Wang He, Qin Yuanbo, Volpicelli-Daley Laura, Swan Laura, Lucast Louise, Khoo Cynthia, Zhang Xiaowu, Li Lin, Abrams Charles S, Sokol Sergei Y, Wu Dianqing
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
Science. 2008 Sep 5;321(5894):1350-3. doi: 10.1126/science.1160741.
The canonical Wnt-beta-catenin signaling pathway is initiated by inducing phosphorylation of one of the Wnt receptors, low-density lipoprotein receptor-related protein 6 (LRP6), at threonine residue 1479 (Thr1479) and serine residue 1490 (Ser1490). By screening a human kinase small interfering RNA library, we identified phosphatidylinositol 4-kinase type II alpha and phosphatidylinositol-4-phosphate 5-kinase type I (PIP5KI) as required for Wnt3a-induced LRP6 phosphorylation at Ser1490 in mammalian cells and confirmed that these kinases are important for Wnt signaling in Xenopus embryos. Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [PtdIns (4,5)P2] through frizzled and dishevelled, the latter of which directly interacted with and activated PIP5KI. In turn, PtdIns (4,5)P2 regulated phosphorylation of LRP6 at Thr1479 and Ser1490. Therefore, our study reveals a signaling mechanism for Wnt to regulate LRP6 phosphorylation.
经典的Wnt-β-连环蛋白信号通路是通过诱导Wnt受体之一低密度脂蛋白受体相关蛋白6（LRP6）的苏氨酸残基1479（Thr1479）和丝氨酸残基1490（Ser1490）磷酸化来启动的。通过筛选人激酶小干扰RNA文库，我们确定Ⅱ型磷脂酰肌醇4激酶α和Ⅰ型磷脂酰肌醇-4-磷酸5激酶（PIP5KI）是哺乳动物细胞中Wnt3a诱导的LRP6在Ser1490处磷酸化所必需的，并证实这些激酶对非洲爪蟾胚胎中的Wnt信号传导很重要。Wnt3a通过卷曲蛋白和蓬乱蛋白刺激磷脂酰肌醇4,5-二磷酸[PtdIns(4,5)P2]的形成，其中后者直接与PIP5KI相互作用并激活PIP5KI。反过来，PtdIns(4,5)P2调节LRP6在Thr1479和Ser1490处的磷酸化。因此，我们的研究揭示了Wnt调节LRP6磷酸化的信号传导机制。
