Xenopus frizzled-4S, a splicing variant of Xfz4 is a context-dependent activator and inhibitor of Wnt/β-catenin signaling

Here we report that the Xenopus frizzled-4 is alternatively spliced to give rise to a putative secreted protein that lacks the seven-transmembrane and the cytoplasmic domains. We performed functional experiments in Xenopus embryos to investigate how this novel splicing variant, Xfz4S, can modulate the Wnt/β-catenin pathway. We show that Xfz4S as well as the extracellular domain of Xfz8 (ECD8) can act as both activators and inhibitors of Wnt/β-catenin signaling dependent on the Wnt ligand presented. The positive regulation of Wnt/β-catenin signaling by the extracellular domains of Frizzled receptors is mediated by the members of low density lipoprotein receptor-related protein (LRP-5/6) that act as Wnt coreceptors.This work provides evidence that the secreted extracellular domains of Frizzled receptors may act as both inhibitors and activators of Wnt signaling dependent on the Wnt ligand presented.Wnts are secreted glycoproteins that control an array of signaling processes in embryos and adult tissues [1-4]. These proteins act through the members of the Frizzled family of seven-transmembrane receptors [5,6]. Wnt and Frizzled interaction leads to the stabilization of cytoplasmic β-catenin, its nuclear translocation and subsequent transcriptional activation of Wnt/β-catenin target genes [1,7]. Two members of low-density lipoprotein receptor-related protein, LRP-5 and -6, act as coreceptors in the Wnt/β-catenin signaling [8-10]. These transmembrane proteins can interact with Wnts and form a ternary complex with Frizzled receptors [9]. This leads to the binding of axin to the cytoplasmic domain of LRP and its recruitment to the membrane [11]. Axin is a scaffolding protein necessary in the cytoplasm for assembly of the protein complex that phosphorylates β-catenin and promotes its degradation by ubiquitin proteasome dependent pathway [12,13]. Recruitment of axin to the membrane by LRP leads to the reduced phosphorylation of β-catenin and subsequent activation of Wnt/β-cat