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PMID:30026314

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Citation

Eubelen, M, Bostaille, N, Cabochette, P, Gauquier, A, Tebabi, P, Dumitru, AC, Koehler, M, Gut, P, Alsteens, D, Stainier, DYR, Garcia-Pino, A and Vanhollebeke, B (2018) A molecular mechanism for Wnt ligand-specific signaling. Science 361

Abstract

Wnt signaling is key to many developmental, physiological, and disease processes in which cells seem able to discriminate between multiple Wnt ligands. This selective Wnt recognition or "decoding" capacity has remained enigmatic because Wnt/Frizzled interactions are largely incompatible with monospecific recognition. Gpr124 and Reck enable brain endothelial cells to selectively respond to Wnt7. We show that Reck binds with low micromolar affinity to the intrinsically disordered linker region of Wnt7. Availability of Reck-bound Wnt7 for Frizzled signaling relies on the interaction between Gpr124 and Dishevelled. Through polymerization, Dishevelled recruits Gpr124 and the associated Reck-bound Wnt7 into dynamic Wnt/Frizzled/Lrp5/6 signalosomes, resulting in increased local concentrations of Wnt7 available for Frizzled signaling. This work provides mechanistic insights into the Wnt decoding capacities of vertebrate cells and unravels structural determinants of the functional diversification of Wnt family members.

Links

PubMed Online version:10.1126/science.aat1178

Keywords

Animals; Brain/blood supply; Brain/cytology; Dishevelled Proteins/metabolism; Endothelial Cells/metabolism; Frizzled Receptors/metabolism; HEK293 Cells; Humans; Ligands; Neovascularization, Physiologic; Protein Binding; Receptors, G-Protein-Coupled/metabolism; Wnt Proteins/metabolism; Wnt Signaling Pathway; Zebrafish

Significance

Annotations

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

DANRE:A0A0U2ULT4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P51142

F

Seeded From UniProt

complete

DANRE:AGRA2

part_of

GO:1990909: Wnt signalosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DANRE:AGRA2

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:WNT7A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Z0J1

F

Seeded From UniProt

complete

XENLA:DVL2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:A0A0U2ULT4

F

Seeded From UniProt

complete

HUMAN:WNT7B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Z0J1

F

Seeded From UniProt

complete

HUMAN:AGRA2

part_of

GO:1990909: Wnt signalosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:AGRA2

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

MOUSE:RECK

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P56706

F

Seeded From UniProt

complete

MOUSE:RECK

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O00755

F

Seeded From UniProt

complete

MOUSE:RECK

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

MOUSE:RECK

enables

GO:1904928: coreceptor activity involved in canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RECK

part_of

GO:1990909: Wnt signalosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RECK

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RECK

enables

GO:0017147: Wnt-protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O00755

F

Seeded From UniProt

complete

Notes

See also

References

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