Wei Qiou, Yokota Chika, Semenov Mikhail V, Doble Brad, Woodgett Jim, He Xi
Program of Neurobiology, Children's Hospital Boston, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2007 May 25;282(21):15903-11. doi: 10.1074/jbc.M701927200. Epub 2007 Mar 30.
R-spondin proteins are newly identified secreted molecules that activate beta-catenin signaling. However, the mechanism of R-spondin action and its relationship with Wnt signaling remain unclear. Here we show that human R-spondin1 (hRspo1) is a high affinity ligand for the Wnt co-receptor LRP6 (K(d) = 1.2 nm). hRspo1 induces glycogen synthase kinase 3-dependent phosphorylation and activation of LRP6. DKK1, an LRP6 antagonist, inhibits hRspo1-induced LRP6 phosphorylation. We further demonstrate that hRspo1 synergizes with Frizzled5 in Xenopus axis induction assays and induces the phosphorylation of Dishevelled, a cytoplasmic component downstream of Frizzled function. Our study reveals interesting similarity and distinction between Wnt and R-spondin signaling.
R-spondin蛋白是新发现的能激活β-连环蛋白信号传导的分泌分子。然而，R-spondin的作用机制及其与Wnt信号传导的关系仍不清楚。在此我们表明，人R-spondin1（hRspo1）是Wnt共受体LRP6的高亲和力配体（解离常数K(d)=1.2纳米）。hRspo1诱导糖原合酶激酶3依赖的LRP6磷酸化和激活。LRP6拮抗剂DKK1抑制hRspo1诱导的LRP6磷酸化。我们进一步证明，在非洲爪蟾轴诱导实验中，hRspo1与卷曲蛋白5协同作用，并诱导卷曲蛋白功能下游的细胞质成分Dishevelled的磷酸化。我们的研究揭示了Wnt和R-spondin信号传导之间有趣的异同。
