PMID:20723538

Citation	von Marschall, Z and Fisher, LW (2010) Secreted Frizzled-related protein-2 (sFRP2) augments canonical Wnt3a-induced signaling. Biochem. Biophys. Res. Commun. 400:299-304
Abstract	Secreted Frizzled-related proteins (sFRP) are involved in embryonic development as well as pathological conditions including bone and myocardial disorders and cancer. Because of their sequence homology with the Wnt-binding domain of Frizzled, they have generally been considered antagonists of canonical Wnt signaling. However, additional activities of various sFRPs including both synergism and mimicry of Wnt signaling as well as functions other than modulation of Wnt signaling have been reported. Using human embryonic kidney cells (HEK293A), we found that sFRP2 enhanced Wnt3a-dependent phosphorylation of LRP6 as well as both cytosolic β-catenin levels and its nuclear translocation. While addition of recombinant sFRP2 had no activity by itself, Top/Fop luciferase reporter assays showed a dose-dependent increase of Wnt3a-mediated transcriptional activity. sFRP2 enhancement of Wnt3a signaling was abolished by treatment with the Wnt antagonist, Dickkopf-1 (DKK1). Wnt-signaling pathway qPCR arrays showed that sFRP2 enhanced the Wnt3a-mediated transcriptional up-regulation of several genes regulated by Wnt3a including its antagonists, DKK1, and Naked cuticle-1 homolog (NKD1). These results support sFRP2's role as an enhancer of Wnt/β-catenin signaling, a result with biological impact for both normal development and diverse pathologies such as tumorigenesis.
Links	PubMed PMC2952323 Online version:10.1016/j.bbrc.2010.08.043
Keywords	Active Transport, Cell Nucleus; Animals; Carrier Proteins/metabolism; Cell Line; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/metabolism; Gene Expression Regulation; Humans; Intercellular Signaling Peptides and Proteins/metabolism; LDL-Receptor Related Proteins/metabolism; Low Density Lipoprotein Receptor-Related Protein-6; Membrane Proteins/metabolism; Mice; Phosphorylation; Protein Stability; Signal Transduction; Transcription, Genetic; Wnt Proteins/antagonists & inhibitors; Wnt Proteins/metabolism; Wnt3 Protein; Wnt3A Protein; beta Catenin/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:WNT3A		GO:0090263: positive regulation of canonical Wnt receptor signaling pathway	ECO:0000314:		P		Figure 1A: Wnt3a increased the total beta-catenin level in HEK293A cells indicating that Wnt3a activates the canonical pathway in the particular cells.	complete
HUMAN:WNT3A		GO:0035413: positive regulation of catenin protein nuclear translocation	ECO:0000314:		P		Figure 1B: induction of beta-catenin protein level upon Wnt3a/sFRP2 showed increased beta-catenin nuclear translocation	complete
HUMAN:WNT3A		GO:0017025: TATA-binding protein binding	ECO:0000314:		F		Figure 1(B): Wnt3a binds to TATA binding protein.	complete
HUMAN:WNT3A		GO:0001934: positive regulation of protein phosphorylation	ECO:0000314:		P		Figure 1(D): Treatment with Wnt3a lead to induced phosphorylation of LRP6. In addition, treatment with both the Wnt3a and sFRP2 enhanced the LRP6 phosphorylation in HEK293A cells.	complete
HUMAN:WNT3A		GO:0045941: positive regulation of transcription	ECO:0000314:		P		Figure 3:When Wnt3a plus sFRP2 were used for treatment of Wnt11 showed enhanced mRNA expression.	complete
HUMAN:WNT3A	enables	GO:0048018: receptor ligand activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:WNT3A	involved_in	GO:0045944: positive regulation of transcription by RNA polymerase II	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:WNT3A	involved_in	GO:0090263: positive regulation of canonical Wnt signaling pathway	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:WNT3A	involved_in	GO:0033138: positive regulation of peptidyl-serine phosphorylation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:WNT3A	involved_in	GO:0060070: canonical Wnt signaling pathway	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:DKK1		GO:0032091: negative regulation of protein binding	ECO:0000314:		P		Figure 2A:DKK1 blocked both Wnt3a and Wnt3a/sFRP2 leading to increased phosphorylation of LRP6	complete
HUMAN:DKK1	involved_in	GO:0033137: negative regulation of peptidyl-serine phosphorylation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:DKK1	involved_in	GO:0000122: negative regulation of transcription by RNA polymerase II	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:DKK1	enables	GO:0048019: receptor antagonist activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
MOUSE:SFRP2		GO:0035413: positive regulation of catenin protein nuclear translocation	ECO:0000314:		P		Figure 1B: induction of beta-catenin protein level upon Wnt3a/sFRP2 showed increased beta-catenin nuclear translocation	complete
MOUSE:SFRP2		GO:0001934: positive regulation of protein phosphorylation	ECO:0000314:		P		Figure 1D: Treatment with both Wnt3a and sFRP2 augmented the LRP6 phosphorylation in HEK293A cells.	complete
MOUSE:SFRP2		GO:0045941: positive regulation of transcription	ECO:0000314:		P		Figure 3:When Wnt3a plus sFRP2 were used for treatment of Wnt11 showed enhanced mRNA expression.	complete
MOUSE:SFRP2	involved_in	GO:0033138: positive regulation of peptidyl-serine phosphorylation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:SFRP2	enables	GO:0048018: receptor ligand activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
MOUSE:SFRP2	involved_in	GO:0045944: positive regulation of transcription by RNA polymerase II	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:SFRP2	involved_in	GO:0090263: positive regulation of canonical Wnt signaling pathway	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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