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PMID:10347172

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Citation

Bafico, A, Gazit, A, Pramila, T, Finch, PW, Yaniv, A and Aaronson, SA (1999) Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling. J. Biol. Chem. 274:16180-7

Abstract

Frizzled related proteins (FRPs) comprise a family of secreted molecules that contain an N-terminal cysteine-rich domain (CRD) highly similar to the CRDs of the frizzled family of membrane-anchored Wnt receptors. FRPs have been shown to interact with Wnt proteins and antagonize Wnt signaling in a Xenopus developmental model. We demonstrated that FRP antagonizes the Wnt-induced increase in uncomplexed beta-catenin in both transient cotransfection and stable transformation models, where Wnt-induced morphological alterations are inhibited as well. We showed further that FRP inhibits Wnt signaling in a paracrine mode using a T-cell factor luciferase reporter to measure Wnt function. Investigation of the mechanisms responsible for FRP inhibition revealed that FRP forms complexes with WNT-1 or WNT-2 through its CRD domain. Transfection analysis with FRPs containing different tags revealed that FRP itself forms complexes and that this ability is conferred by its CRD domain. Finally, we demonstrated by cotransfection that FRP forms complexes with a prototype frizzled. All of these findings are consistent with a model by which FRP inhibits Wnt signaling through interactions with Wnt and/or formation of nonfunctional complexes with the frizzled receptor.

Links

PubMed

Keywords

Animals; Glycoproteins; Ligands; Platelet-Derived Growth Factor/metabolism; Protein Conformation; Proteins/metabolism; Proto-Oncogene Proteins/metabolism; Signal Transduction; Transfection; Wnt Proteins; Wnt1 Protein; Wnt2 Protein; Xenopus; Xenopus Proteins; Zebrafish Proteins

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:FZD6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8N474

F

Seeded From UniProt

complete

HUMAN:WNT2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8N474

F

Seeded From UniProt

complete

HUMAN:SFRP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O60353

F

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0008285: negative regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

enables

GO:0017147: Wnt-protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P09544

F

Seeded From UniProt

complete

HUMAN:SFRP1

enables

GO:0005109: frizzled binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O60353

F

Seeded From UniProt

complete

HUMAN:SFRP1

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8N474

F

Seeded From UniProt

complete

HUMAN:SFRP1

located_in

GO:0062023: collagen-containing extracellular matrix

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT2

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT2

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FZD6

enables

GO:0042813: Wnt-activated receptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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