Cell‐to‐Cell Signalling in Development: Wnt Signalling

Abstract

Wnt signalling is an important cell‐to‐cell signalling mechanism, which is generally conserved among multicellular animals. Wnt signalling operates in the embryo and in adult stem cells, but also in human cancers. Frizzled receptors in the cell membrane are critical functional intermediaries between the extracellular Wnt signal and diverse signal transduction mechanisms that can be activated inside different responding cells. Coreceptors are involved in selecting more specific intracellular signal transduction mechanisms. Frizzled receptors and other Wnt signalling molecules are localised in cells to coordinate planar cell polarity in epithelial tissues and also to regulate morphogenetic movements in embryos. A well‐studied intracellular Wnt signal transduction mechanism promotes stabilisation and nuclear localisation of the protein β‐catenin to regulate transcription of specific target genes by interacting with deoxyribonucleic acid (DNA)‐binding transcription factor proteins, such as the TCF/LEF proteins.

Key Concepts:

  • Wnt signalling functions in the embryo, to regulate stem cells and in disease such as cancer.

  • Wnt signalling mechanisms regulate important cellular processes, such as cell fate specification, cell proliferation, cell differentiation, axon guidance and morphogenesis.

  • Wnt proteins are lipid‐modified secreted signals.

  • Frizzled proteins function as cell membrane receptors for Wnt signals.

  • Wnt/Frizzled signalling activates a network of diverse intracellular signal transduction pathways.

  • One conserved branch of Wnt signal transduction causes stabilisation and nuclear localisation of the protein β‐catenin.

  • Nuclear β‐catenin regulates transcription of specific target genes by interacting with DNA‐binding proteins, such as TCF/LEF proteins.

  • Other, β‐catenin‐independent Wnt signal transduction mechanisms also regulate the cytoskeleton and planar cell polarity.

  • Feedback regulation and cross‐regulation between different Wnt signal transduction branches is characteristic of Wnt signalling.

Keywords: β‐catenin; GSK3; Axin; APC; planar cell polarity; G‐protein‐coupled receptor; morphogenesis; cilia; cytoskeleton; TCF/LEF

Figure 1.

WNT receptors in the cell membrane: Wnt proteins (WNT) are extracellular signals, whose protein structure has been compared to a left hand, with thumb and index finger holding the extracellular domain of the Frizzled (FZD) receptors, and the palm of the hand resting on a coreceptor (Coreceptor). The intracellular domains of the FZD 7‐transmembrane receptor interact with the cytoplasmic Dishevelled (DVL) protein, which mediates many of the intracellular signal transduction mechanisms that are triggered by Wnt signalling.

Figure 2.

WNT signalling molecules become localised to regulate planar cell polarity (PCP): Epithelial tissues have an apical to basal polarity and often also a planar cell polarity. Six cells in an epithelium are illustrated in perspective. Components of Wnt signalling mechanisms, particularly Frizzled receptors (F) and Dishevelled (D), become localised to one side of cells within the plane of the epithelial tissue (here illustrated on the right side of cells). Other molecules, such as Van Gogh (V) and Prickle (P), become localised on the opposite (here left) side of the same cell and facing Frizzled and Dishevelled in adjacent cells. Many other molecules that are not illustrated here are required to set up and maintain this polarised localisation of Frizzled and Dishevelled, which activates localised intracellular signal transduction mechanisms to regulate above all the organisation of the actin cytoskeleton.

Figure 3.

β‐catenin‐dependent Wnt signal transduction mechanisms: In the absence of extracellular Wnt signalling (‘off’ position on the left), a cytoplasmic β‐catenin destruction complex is assembled around Axin, which causes degradation of β‐catenin. With Wnt signalling (‘on’ position on the right), the extracellular Wnt signal binds Frizzled and LRP5/6 cell membrane receptors to cause assembly of a multiprotein complex containing Dishevelled and Axin; now stable cytoplasmic β‐catenin can enter the cell nucleus to assemble transcription activation complexes with, for instance, T‐cell factor (TCF)/lymphoid enhancer‐binding factor (LEF) DNA‐binding proteins. Abbreviations: A, Axin; APC, adenomatous polyposis coli; β, β‐catenin; D, Dishevelled; F, Frizzled; G, Glycogen synthase kinase (GSK3); L, LRP5/6; T, TCF/LEF and W, Wnt signal. Additional components in protein complexes were not drawn here for simplification.

Figure 4.

TCF transcriptional switch on WNT/β‐catenin target genes: TCF/LEF DNA‐binding factors (TCF) can function as transcriptional repressors (left) or as transcriptional activators (right). TCF proteins bind to Wnt response elements (WRE) in promoters and enhancers of Wnt target genes. The high mobility group protein domain interacts with a core site (approximately CTTTGA), whereas some TCF proteins encode an additional DNA‐binding domain (C‐Clamp) which interacts with GC‐rich DNA sequences nearby, called helper site. With Wnt signalling in the ‘off’ position (left), TCF proteins interact with transcriptional corepressors (R), particularly members of the Groucho/TLE family of proteins. When Wnt signalling is in the ‘on’ position (right), nuclear β‐catenin induces a transcriptional switch when binding to TCF proteins by disrupting Groucho/TLE binding or function and recruiting transcriptonal coactivators (A), such as CBP and p300, to the TCF/β‐catenin protein complex, which now functions as a multiprotein transcriptional activator. Additional components in protein complexes were not drawn here for simplification.

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Further Reading

Hoppler S and Moon RT (2014) Wnt Signaling in Development and Disease: Molecular Mechanisms and Biological Functions. Hoboken, New Jersey: Wiley‐Blackwell Publishers. ISBN: 978‐1‐118–44416‐0.

Nusse R, He X and van Amerongen R (2013) Wnt signaling. Cold Spring Harbor Perspectives in Biology, 454 pp. ISBN: 978‐1‐936113‐23‐1.

Web Links

Wnt Homepage curated by Roel Nusse. http://www.stanford.edu/group/nusselab/cgi‐bin/wnt/main

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Hoppler, Stefan, and Nakamura, Yukio(Apr 2014) Cell‐to‐Cell Signalling in Development: Wnt Signalling. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002331.pub2]