You Wnt some, you lose some: oncogenes in the Wnt signaling pathway

https://doi.org/10.1016/S0959-437X(02)00012-6Get rights and content

Abstract

The highly regulated Wnt signaling cascade plays a decisive role during embryonic patterning and cell-fate determination. The inappropriate expression of Wnt target genes, resulting from deregulation of this pathway, is also implicated in tumorigenesis. Thus, regulation of this pathway is of paramount importance. The Wnt signals are extracellularly regulated by a diverse group of antagonists, cofactors and coreceptors. In the cytoplasm, β-catenin, a key effector of the Wnt signaling cascade, is highly regulated by a large and fascinating complex of proteins. In the nucleus, activation of target genes is regulated by a complex interplay of activators, repressors and other proteins. Recently, new factors in this pathway have been identified and the interplay and mechanisms of action of key players have been better characterized. Collectively, this represents an important step forward in our understanding of the role of Wnt signaling in development and oncogenesis.

Introduction

The development of a complex multicellular organism from a fertilized egg is tightly controlled in space and time by a complex and sophisticated interplay of signaling pathways. This is particularly true for signaling pathways in which secreted factors, such as members of the Hedgehog, TGF-β and Wnt families, are involved. It is of crucial importance that these signaling pathways are regulated at multiple levels. Indeed, breakdown of this regulation, leading to inappropriate activation of the signaling pathways, has been implicated in cancer. The highly conserved Wnt proteins, which drive the Wnt signaling pathway, determine many important cell-fate decisions throughout development by controlling gene expression, cell behavior, cell adhesion and cell polarity. In this review we look at recent developments regarding the role of the three (putative) oncogenes Wnt, β-catenin and Legless/Bcl9 in the Wnt signaling pathway (Figure 1).

Section snippets

The Wnt signaling pathway

The binding of a particular secreted Wnt ligand to its corresponding receptor, a member of the Frizzled (Frz) family, activates the highly conserved Wnt signaling pathway [1] (Figure 1). Depending on the specific Wnt/Frz signal received, the downstream Wnt pathway subsequently diversifies into at least three branches, which crossregulate one another as well as interacting with other signaling networks 1., 2., 3., 4..

Three pathways are activated by Wnt: the Wnt/Ca2+ pathway, the planar cell

The canonical Wnt pathway: a brief overview

The Wnt canonical pathway regulates, through a core set of evolutionarily highly conserved proteins, the ability of the multi-functional protein and proto-oncogene β-catenin to activate the transcription of specific target genes [1]. In the absence of Wnt signals, free cytoplasmic β-catenin is actively targeted for degradation. This destruction is triggered by the phosphorylation of β-catenin at its amino terminus following its association with a multiprotein complex containing, amongst other

The prototypical oncogene Wnt: receptor regulation

Members of the Wnt family have distinct biological roles. The first-identified Wnt gene, mouse Wnt1, was pinpointed by virtue of its ability to induce mammary tumors when expressed ectopically in mice [30]. Since then, numerous Wnt genes have been identified. In particular, Wnts have been implicated in the abnormal proliferation of human breast tissue. The mechanism of action of these various Wnt genes, and the way in which they are regulated, is complex. Several membrane-associated proteins

The oncogene β-catenin: regulation

The serine/threonine kinase GSK3β binds to and phosphorylates several proteins involved in the Wnt pathway and is instrumental in the down-regulation of β-catenin, which it achieves by earmarking this protein for degradation by β-Trcp. The importance of the phosphorylation of β-catenin in controlling degradation is further underscored by the observation that the target phosphorylation sites (Ser45, Thr41, Ser37 and Ser33) are frequently mutated in human colorectal cancer, melanomas and several

The putative oncogene Legless: activation of Wnt target genes

It is well established that the formation of a β-catenin/TCF complex in combination with other factors — which include the CBP/p300 acetyltransferase, the TATA binding protein, DNA helicase Pontin52 and/or Brg-1 — is a prerequisite for the efficient activation of target genes. However, its mechanism of action remains poorly understood [45].

Two novel nuclear components of the β-catenin/TCF complex have recently been identified. Epistasis analysis of the β-catenin binding protein Legless in

Conclusions

The Wnt signaling cascade plays a decisive role in development, and deregulation causes cancer. Ongoing studies in this exciting field are revealing additional players in the Wnt pathway and are highlighting the complex and multifaceted nature of known participants. Although it is apparent that our knowledge of this pathway is increasing rapidly, many questions regarding regulation, specificity, and interactions with other signaling cascades require answering. The results will undoubtedly

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

We apologize to all researchers whose work we could not cite due to strict space constraints. We would like to thank ME van Gijn for helpful comments on the manuscript.

References (50)

  • S. Amit et al.

    axin mediated CK1 phosphorylation of β-catenin a molecular switch

    Genes Dev.

    (2002)
  • D.E. Kang et al.

    Presenilin couples the paired phosphorylation of β-catenin independent of axin: implications for β-catenin activation in tumorigenesis

    Cell

    (2002)
  • A. Hurlstone et al.

    T-cell factors: turn-ons and turn-offs

    EMBO J.

    (2002)
  • M. Peifer et al.

    Wnt signalling in oncogenesis and embryogenesis — a look outside the nucleus

    Science

    (2000)
  • T. Saneyoshi et al.

    The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos

    Nature

    (2002)
  • R. Winklbauer et al.

    Frizzled-7 signaling controls tissue separation during Xenopus

    Nature

    (2001)
  • S. Sokol

    A role for Wnts in morphogenesis and tissue polarity

    Nat. Cell. Biol.

    (2000)
  • B. Lu et al.

    Adherens junctions inhibit asymmetric division in the Drosophila epithelium

    Nature

    (2001)
  • W. Zeng et al.

    Naked cuticle encodes an inducible antagonist of Wnt signaling

    Nature

    (2000)
  • M. Park et al.

    The planar cell-polarity gene stbm regulates cell behaviour and cell fate in vertebrate embryos

    Nat. Cell. Biol.

    (2001)
  • T. Schwarz-Romond et al.

    The ankyrin repeat protein Diversin recruits Casein kinase Iε to the β-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling

    Genes Dev.

    (2002)
  • T.-Q. Sun et al.

    PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling

    Nat. Cell. Biol.

    (2001)
  • B.N.R. Cheyette et al.

    Dapper, a Dishevelled-associated antagonist of β-Catenin and JNK signaling, is required for notochord formation

    Dev. Cell.

    (2002)
  • J. Jiang et al.

    Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb

    Nature

    (1998)
  • J. Roose et al.

    The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors

    Nature

    (1998)
  • Cited by (211)

    • The maternal control in the embryonic development of zebrafish

      2017, General and Comparative Endocrinology
    • Wnt/β Catenin-Mediated Signaling Commonly Altered in Colorectal Cancer

      2016, Progress in Molecular Biology and Translational Science
    View all citing articles on Scopus
    View full text