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PMID:19910923

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Citation

Sato, A, Yamamoto, H, Sakane, H, Koyama, H and Kikuchi, A (2010) Wnt5a regulates distinct signalling pathways by binding to Frizzled2. EMBO J. 29:41-54

Abstract

Wnt5a regulates multiple intracellular signalling cascades, but how Wnt5a determines the specificity of these pathways is not well understood. This study examined whether the internalization of Wnt receptors affects the ability of Wnt5a to regulate its signalling pathways. Wnt5a activated Rac in the beta-catenin-independent pathway, and Frizzled2 (Fz2) and Ror1 or Ror2 were required for this action. Fz2 was internalized through a clathrin-mediated route in response to Wnt5a, and inhibition of clathrin-dependent internalization suppressed the ability of Wnt5a to activate Rac. As another action of Wnt5a, it inhibited Wnt3a-dependent lipoprotein receptor-related protein 6 (LRP6) phosphorylation and beta-catenin accumulation. Wnt3a-dependent phosphorylation of LRP6 was enhanced in Wnt5a knockout embryonic fibroblasts. Fz2 was also required for the Wnt3a-dependent accumulation of beta-catenin, and Wnt5a competed with Wnt3a for binding to Fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway. This inhibitory action of Wnt5a was not affected by the impairment of clathrin-dependent internalization. These results suggest that Wnt5a regulates distinct pathways through receptor internalization-dependent and -independent mechanisms.

Links

PubMed PMC2808370 Online version:10.1038/emboj.2009.322

Keywords

Animals; Binding, Competitive; CHO Cells; Cell Line; Clathrin/metabolism; Cricetinae; Cricetulus; Frizzled Receptors/metabolism; HeLa Cells; Humans; L Cells (Cell Line); LDL-Receptor Related Proteins/metabolism; Low Density Lipoprotein Receptor-Related Protein-6; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Protein Binding; Proto-Oncogene Proteins/antagonists & inhibitors; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins/pharmacology; RNA, Small Interfering/genetics; Receptors, G-Protein-Coupled/metabolism; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Signal Transduction; Wnt Proteins/antagonists & inhibitors; Wnt Proteins/deficiency; Wnt Proteins/genetics; Wnt Proteins/metabolism; Wnt Proteins/pharmacology; Wnt3 Protein; Wnt3A Protein; beta Catenin/metabolism; rac GTP-Binding Proteins/metabolism

Significance

Annotations

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

MOUSE:LRP6

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98956

P

Seeded From UniProt

complete

MOUSE:WNT5A

enables

GO:0005109: frizzled binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:1888513)

Seeded From UniProt

complete

MOUSE:WNT3A

enables

GO:0005109: frizzled binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:1888513)

Seeded From UniProt

complete

MOUSE:WNT5A

enables

GO:0005109: frizzled binding

ECO:0000314: direct assay evidence used in manual assertion

F

has_input:(MGI:MGI:1888513)

Seeded From UniProt

complete

MOUSE:WNT5A

acts_upstream_of_or_within

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1888513
MGI:MGI:98956

P

Seeded From UniProt

complete

MOUSE:WNT3A

enables

GO:0005109: frizzled binding

ECO:0000314: direct assay evidence used in manual assertion

F

has_input:(MGI:MGI:1888513)

Seeded From UniProt

complete

MOUSE:WNT3A

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1298218
MGI:MGI:1888513

P

Seeded From UniProt

complete


See also

References

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