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Proximal events in Wnt signal transduction

Nature Reviews Molecular Cell Biology volume 10, pages 468–477 (2009)Cite this article

Key Points

  • Whereas the cytoplasmic and nuclear steps of the Wnt signalling pathway are fairly well understood, gaps remain in our understanding of how Wnt receptors transduce information to the nucleus of the cell.

  • Although the Frizzled receptors for Wnt proteins are seven transmembrane domain proteins that are generally thought to function by activating heterotrimeric G proteins, whether they engage G proteins has been debated, despite a growing number of biochemical, functional and genetic studies.

  • Lateral signalling from Frizzled receptors to low density lipoprotein receptor-related protein 5 (LRP5) or LRP6, involves the recruitment of Dishevelled proteins and the Axin–glycogen synthase kinase 3 (GSK3) complex, and the phosphorylation of LRP5 or LRP6 by GSK3 and casein kinase 1γ (CK1γ). The recruitment of axin to phosphorylated LRP5 or LRP6 disassembles the degradation complex and leads to β-catenin stabilization.

  • Recently, non-Frizzled receptors for Wnt have been identified. The receptor Tyr kinases ROR2 and RYK can physically interact with Wnt proteins, impinge on known Frizzled-mediated pathways or regulate cellular processes of their own.

  • The primary cilium has recently been found to regulate many cell signalling processes. With respect to Wnt pathways, cilia positively regulate β-catenin-independent signalling and negatively constrain β-catenin-dependent signalling.

Abstract

The Wnt family of secreted ligands act through many receptors to stimulate distinct intracellular signalling pathways in embryonic development, in adults and in disease processes. Binding of Wnt to the Frizzled family of receptors and to low density lipoprotein receptor-related protein 5 (LRP5) or LRP6 co-receptors stimulates the intracellular Wnt–β-catenin signalling pathway, which regulates β-catenin stability and context-dependent transcription. This signalling pathway controls many processes, such as cell fate determination, cell proliferation and self-renewal of stem and progenitor cells. Intriguingly, the transmembrane receptor Tyr kinases Ror2 and Ryk, as well as Frizzled receptors that act independently of LRP5 or LRP6, function as receptors for Wnt and activate β-catenin-independent pathways. This leads to changes in cell movement and polarity and to the antagonism of the β-catenin pathway.

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Figure 1: Wnt–β-catenin signalling in metazoans.
Figure 2: β-Catenin-dependent Wnt signalling.
Figure 3: β-Catenin-independent Wnt pathways.
Figure 4: Lateral signalling between Frizzled and LRPs.
Figure 5: Non-Frizzled receptors for Wnt ligands.
Figure 6: Cilia regulate Wnt signalling.

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Acknowledgements

S.A. is the recipient of a Canada Research Chair in Functional Architecture of Signal Transduction and is supported by the Canadian Institute of Health Research and the Cancer Research Society. R.T.M. is an investigator of the Howard Hughes Medical Institute. The authors thank V. Voronina for reading the manuscript.

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  1. Leslie Dan Faculty of Pharmacy and the Department of Biochemistry, University of Toronto, Ontario, M5S 3M2, Canada

    Stephane Angers

  2. Department of Pharmacology and the Institute for Stem Cell and Regenerative Medicine, Howard Hughes Medical Institute, University of Washington School of Medicine, BOX 358056, Seattle, 98195, Washington, USA

    Randall T. Moon

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Stephane Angers does not declare competing financial interests. Randall T. Moon is a consultant for Fate Therapeutics.

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DATABASES

OMIM

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polydactyly

situs inversus

Entrez Protein

CAM-1

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Glossary

Glycoproteins

A protein that is post-translationally modified with oligosaccharide moieties.

Ubiquitylation

A post-translational modification of proteins that involves the covalent linkage of the small protein ubiquitin to target Lys residues. Ubiquitylation commonly leads to polypeptides being recognized by the 26S proteasome for degradation, but can also modify the function of target proteins.

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The coordinated organization of individual cells, with respect to the plane of a single sheet of cells.

Convergent extension movement

A specialized morphogenetic cell movement that consists of the mediolateral convergence of mesodermal cells and of their intercalation perpendicular to the axis of elongation. The net result of these cell movements is the elongation of the embryonic body axis.

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A guanine nucleotide-binding protein, comprising an α-subunit and a βγ-dimer, that is activated following the activation of a G protein-coupled receptor.

Primitive endoderm

Early differentiated cells that form an epithelial structure, which covers the pluripotent cells of the inner cell mass. The primitive endoderm develops into the visceral endoderm that covers the epiblast and the parietal endoderm that lines the blastocoel cavity.

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A toxin secreted by the bacterium Bordetella pertussis. Pertussis toxin functions by catalysing the ADP-ribosylation of Gαi, Gαo and Gαt, which prevents their association with cognate G protein-coupled receptors and thus inhibits signalling.

Ommatidium

The eye of insects is composed of units called ommatidia. The ommatidium contains photoreceptor and pigment cells.

Hypomorphic clone

A group of cells in which the same gene is mutated, and in which the mutation only partially affects the biological activity controlled by the gene product.

Guanine nucleotide-exchange factor

A protein that interacts with, and activates, G proteins by promoting the exchange of GDP for GTP.

Epistasis experiment

An approach used to determine whether two genes function in the same biological pathway. Epistasis experiments also give information on the order in which the genes function.

Gastrulation

An embryonic process characterized by extensive cell movements that establishes the three germ layers: endoderm, ectoderm and mesoderm.

Signalosome

A group of proteins that assemble together to carry out a specific signalling task.

Animal cap

An explant dissected from the animal pole of a blastula stage embryo that contains pluripotent cells.

Homeodomain protein

Member of a family of transcription factors that direct morphogenesis during development.

Commissural neuron

A neuron that extends axons across the ventral midline to transfer sensory information from one side of the body to the other in bilaterally symmetrical organisms.

Basal body

An organelle anchored at the plasma membrane and found at the base of primary cilia. It serves as a nucleation site for the growth of microtubules.

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Angers, S., Moon, R. Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol 10, 468–477 (2009). https://doi.org/10.1038/nrm2717

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