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PMID:20723538

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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

Significance

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


See also

References

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