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Cell Commun Signal October 19, 2005; 3 12.

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

Swain RK , Katoh M , Medina A , Steinbeisser H .

Secreted Frizzled related proteins (SFRPs) are extracellular regulators of Wnt signaling. These proteins contain an N-terminal cysteine rich domain (CRD) highly similar to the CRDs of the Frizzled family of seven-transmembrane proteins that act as Wnt receptors. SFRPs can bind to Wnts and prevent their interaction with the Frizzled receptor. Recently it has been reported that a splice variant of human Frizzled-4 (FZD4S) lacking the transmembrane and the cytoplasmic domains of Frizzled-4 can activate rather than inhibit Wnt-8 activity in Xenopus embryos. This indicates that secreted CRD containing proteins such as Frizzled ecto-domains and SFRPs may not always act as Wnt inhibitors. It is not known how FZD4S can activate Wnt/beta-catenin signaling and what biological role this molecule plays in vivo. 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/beta-catenin pathway. We show that Xfz4S as well as the extracellular domain of Xfz8 (ECD8) can act as both activators and inhibitors of Wnt/beta-catenin signaling dependent on the Wnt ligand presented. The positive regulation of Wnt/beta-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.

PubMed ID: 16236168
PMC ID: PMC1291380
Article link: Cell Commun Signal

Species referenced: Xenopus
Genes referenced: akr1c2 ctnnb1 dkk1 dvl1 dvl2 fzd4 fzd7 fzd8 lrp1 lrp6 myc nodal3.1 nodal3.2 odc1 wnt11b wnt3a wnt4 wnt5a wnt8a wnt8b

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References [+] :
Aberle, beta-catenin is a target for the ubiquitin-proteasome pathway. 1997, Pubmed