R-spondins Signal Like Wnts, Sort Of

Wnt proteins are lipid-modified secreted molecules that initiate signaling by interacting with a receptor complex that includes the serpentine receptor Frizzled and low-density lipoprotein receptor—related protein 5 (LRP5) or LRP6. Wnt receptor activation leads to stabilization of β-catenin, which accumulates in the nucleus and activates transcription of Wnt target genes. Roof plate-specific spondins (R-spondins) are proteins unrelated in sequence to Wnts that, like Wnts, are implicated in regulation of development and that also activate signaling through β-catenin. Conflicting reports have been published as to whether R-spondins use the same receptors as Wnts and whether they bind to Frizzled or LRP6, both, or neither. Wei et al . present data showing that human R-spondin1 (hRspo1) binds to cultured human embryonic kidney (HEK293T) cells transfected with LRP6. Solid-phase binding assays showed that hRspo1 bound to the extracellular domain of LRP6 with high affinity (K d , 1.2 nM) but showed little if any binding to Frizzled. The hRspo1 protein also induced phosphorylation of LRP6 (as does Wnt). hRspo1 had synergistic effects with Wnt3A on phosphorylation of LRP6 in HEK293T cells and on phosphorylation of endogenous LRP6 in mouse embryo fibroblasts. R-spondins thus appear to work differently from Wnts in some ways (Wnts bind with high affinity to Frizzled, with weak or no binding to LRP6), but both ligands activate similar downstream signaling events. Furthermore, expression of R-spondins is stimulated by Wnts, leading the authors to propose that R-spondins may act in a positive feedback loop that reinforces Wnt signaling during development. Q. Wei, C. Yokota, M. V. Semenov, B. Doble, J. Woodgett, X. He, R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and β-catenin signaling. J. Biol. Chem. 282 , 15903-15911 (2007). [Abstract] [Full Text]