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The complex world of WNT receptor signalling

Key Points

  • There is bewildering complexity in WNT signal transduction at the cell surface. 19 WNT proteins couple to more than 15 receptors and co-receptors in seven protein families: Frizzled, low-density lipoprotein receptor-related protein 5 (LRP5) and LRP6, receptor Tyr kinase-like orphan receptor 1 (ROR1) and ROR2, protein Tyr kinase 7 (PTK7), receptor Tyr kinase (RYK), muscle skeletal receptor Tyr kinase (MUSK) and the heparan sulphate proteoglycans syndecan and glypican.

  • Frizzled proteins act as principal WNT receptors and recruit different co-receptors to engage specific subpathways.

  • WNT receptors and co-receptors are regulated intracellularly by phosphorylation, proteolytic processing and endocytosis.

  • Endocytosis is a key mechanism, and WNT signalling requires endocytosis, endosomal signalosomes and multivesicular bodies.

  • Agonists (R-spondins) and antagonists (Dickkopf-related protein 1 (DKK1) and Kremen) regulate receptor and co-receptor internalization to modulate WNT signalling.

  • The R-spondin family of WNT agonists acts via downstream transmembrane proteins, inlcuding syndecans, Leu-rich repeat-containing G-protein coupled receptor 4 (LGR4) and LGR6 and transmembrane E3 ubiquitin ligases RNF43 and ZNRF3.

Abstract

30 years after the identification of WNTs, their signal transduction has become increasingly complex, with the discovery of more than 15 receptors and co-receptors in seven protein families. The recent discovery of three receptor classes for the R-spondin family of WNT agonists further adds to this complexity. What emerges is an intricate network of receptors that form higher-order ligand–receptor complexes routing downstream signalling. These are regulated both extracellularly by agonists such as R-spondin and intracellularly by post-translational modifications such as phosphorylation, proteolytic processing and endocytosis.

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Figure 1: WNT signalling pathways.
Figure 2: WNT receptors and co-receptors.
Figure 3: Crystal structure of the wnt8–Frizzled 8 CRD complex.
Figure 4: LRP6 signalosomes, acidification and MVBs.
Figure 5: Model for R-spondin–WNT signalling.

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Acknowledgements

The author thanks C. Janda and C. Garcia for providing the WNT–Frizzled CRD structure and apologizes to those authors whose work could not be cited owing to space limitations.

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FURTHER INFORMATION

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SMART database

Glossary

Embryonic axis

The ensemble of head-to-tail structures of early embryos.

Segmentation

An embryonic process that divides the embryo or parts of it into repetitive segments.

Planar cell polarity

(PCP). Cell polarity within the plane of an epithelial sheet.

Gastrulation

The morphogenetic process whereby embryos acquire the germ layers.

Stereocilia

Tapered, finger-like projections from hair cells of the inner ear that respond to mechanical displacement with alterations in membrane potential and thereby mediate sensory transduction.

Caveolin

A membrane protein that is part of specialized rafts that form flask-shaped, cholesterol-rich invaginations of the plasma membrane. These mediate the uptake of extracellular material and are probably involved in cell signalling.

Clathrin-dependent endocytosis

A pathway that mediates the internalization of plasma membrane proteins. Receptor clustering in membrane domains containing a polymeric clathrin coat and a complex of adaptor proteins and GTPases leads to membrane invagination and scission to form a clathrin-coated vesicle containing the internalized receptors.

Furin domains

Protein domains of unknown function that are found in the protease furin and in non-proteases.

Thrombospondin type I domain

A protein domain that is found in thrombospondin 1 and in non-matrix proteins. This domain binds to heparan sulphate proteoglycans.

Convergent extension

A process during gastrulation in which layers of cells converge and extend by a rearrangement of the cells of the ventral part of the epithelium towards the ventral midline.

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Niehrs, C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13, 767–779 (2012). https://doi.org/10.1038/nrm3470

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