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J Biol Chem
2007 May 25;28221:15903-11. doi: 10.1074/jbc.M701927200.
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R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling.
Wei Q
,
Yokota C
,
Semenov MV
,
Doble B
,
Woodgett J
,
He X
.
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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.
FIGURE 7.
hRspo1 induces axis duplication and Xnr3 expression in the presence of LRP6 or Frizzled5 in Xenopus. A, hRspo1 induces axis duplication when co-injected with LRP6 or Frizzled5. mRNA was injected into the ventral marginal two cells at the 4-8-cell stage. The arrowhead indicates the location of the secondary axis. Note the complete axis duplication in the case of hRspo1 plus Frizzled5. B, summary of data from co-injection experiments. The white bar indicates the percentage of injected embryos that had trunk-tail type of secondary structures. The black bar indicates the percentage of injected embryos that had the secondary head structures. n, number of embryos injected/examined. un inj indicates not injected. C, Xnr3 was induced synergistically in the animal caps by co-injection of hRspo1 and LRP6 or Frizzled5. mRNA was injected into the animal pole of two-cell stage embryos, and the animal caps were dissected at stage 9.5 and cultured until stage 10.5 for RT-PCR analysis. PCR of samples without reverse transcription (RT-) was used as negative control showing no contamination of genomic DNA. The whole embryo (WE) was used as a positive control for RT-PCR. RT-PCR of EF-1α was used as a loading control.
