Abstract
BackgroundSecreted frizzled related proteins (SFRPs) are multifunctional modulators of Wnt and BMP (Bone Morphogenetic Protein) signalling necessary for the development of most organs and the homeostasis of different adult tissues. SFRPs fold in two independent domains: the cysteine rich domain (SfrpCRD) related to the extracellular portion of Frizzled (Fz, Wnt receptors) and the Netrin module (SfrpNTR) defined by homologies with molecules such as Netrin-1, inhibitors of metalloproteinases and complement proteins. Due to its structural relationship with Fz, it is believed that SfrpCRD interferes with Wnt signalling by binding and sequestering the ligand. In contrast, the functional relevance of the SfrpNTR has been barely addressed.ResultsHere, we combine biochemical studies, mutational analysis and functional assays in cell culture and medaka-fish embryos to show that the Sfrp1NTR mimics the function of the entire molecule, binds to Wnt8 and antagonizes Wnt canonical signalling. This activity requires intact tertiary structure and is shared by the distantly related Netrin-1NTR. In contrast, the Sfrp1CRD cannot mirror the function of the entire molecule in vivo but interacts with Fz receptors and antagonizes Wnt8-mediated β-catenin transcriptional activity.ConclusionOn the basis of these results, we propose that SFRP modulation of Wnt signalling may involve multiple and differential interactions among Wnt, Fz and SFRPs.
Highlights
Secreted frizzled related proteins (SFRPs) are multifunctional modulators of Wnt and Bone morphogenetic protein (BMP) (Bone Morphogenetic Protein) signalling necessary for the development of most organs and the homeostasis of different adult tissues
If Sfrp1NTR can mimic the effect of the entire molecule, it should be able to rescue the effects of Mo interference
Sfrp1NTR effects are shared by distantly related Netrin-related motif (NTR) and require intact tertiary structure To explore this possibility further, we investigated whether the relevance of the NTR domain in antagonizing Wnt ligands could be extended to other SFRP family members or even to distantly related NTR domains [11]
Summary
Secreted frizzled related proteins (SFRPs) are multifunctional modulators of Wnt and BMP (Bone Morphogenetic Protein) signalling necessary for the development of most organs and the homeostasis of different adult tissues. Secreted frizzled related proteins (SFRPs) compose a family of soluble factors widely involved in the control of embryonic development and the homeostasis of adult tissues Members of this family were independently isolated using a variety of approaches and immediately proposed as Wnt signalling inhibitors because of their ability to interfere with Wnt-induced embryonic axis duplication and forebrain development in Xenopus [1,2]. The SfrpCRD contains ten cysteines with a pattern of five disulfide bridges identical to that of the extracellular CRD of Fz [6,7] Due to this structural relationship, it is generally assumed that Sfrp-mediated Wnt signalling inhibition results from the interaction between the ligand and SfrpCRD, which has been shown to immunoprecipitate with Wnt and Wnt2 [8,9]. SfrpCRD can form homo- and heterodimers with the CRD domain of Fz receptors [8,10], suggesting potential alternative mechanisms of action
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