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Review
. 2014 Jul;13(7):513-32.
doi: 10.1038/nrd4233.

Can we safely target the WNT pathway?

Michael Kahn  1
Affiliations
Review

Can we safely target the WNT pathway?

Michael Kahn. Nat Rev Drug Discov. 2014 Jul.

Abstract

WNT-β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.

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Conflict of interest statement

Competing interests statement

The author declares competing interests: see Web version for details.

Figures

Figure 1
Figure 1. A simplified representation of the canonical WNT–β-catenin signalling cascade
The WNT–β-catenin signalling cascade has crucial roles in cell fate, proliferation, survival and migration. In the absence of extracellular WNT glycoproteins, a destruction complex — including the proteins adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β) and AXIN — phosphorylates β-catenin, targeting it for ubiquitylation and proteasomal degradation. The binding of WNTs to Frizzled receptors and the co-receptors LRP5 (low-density lipoprotein receptor-related protein 5) and LRP6 relays a signal through Dishevelled (DVL), which results in inhibition of the destruction complex and nuclear entry of β-catenin. In the nucleus, β-catenin acts as a bridge between members of the T cell factor (TCF) family of transcription factors and the basal transcriptional apparatus via co-activators (CREB-binding protein (CBP), E1A-associated protein p300, the co-activator Pygopus (PYGO), B cell lymphoma 9 (BCL-9), and so on). Over the past decade, numerous studies have identified inhibitors at various points along the pathway, a few of which have recently entered clinical trials. These are discussed in detail within the main text. CK1α, casein kinase 1α; CRD, cysteine-rich domain; MBOAT, membrane-bound O-acyltransferase.
Figure 2
Figure 2. WNT signalling in stem cells
This figure shows the dichotomous roles of WNT signalling in the expansion and maintenance of potency in stem cells, as well as in the initiation of differentiation and lineage commitment. Frizzled and low-density lipoprotein receptor-related proteins (LRPs) on the surface of stem cells bind WNTs to regulate the nuclear translocation of β-catenin and activation of its transcriptional role in stem cell gene expression via recruitment of the kynurenine aminotransferase 3 (KAT3) co-activators CREB-binding protein (CBP) or E1A-associated protein p300 (part a). Enzymatic interaction of the transmembrane E3 ligases RING finger protein 43 (RNF43) and zinc/RING finger protein 3 (ZNRF3) can — through a negative feedback loop — lead to abrogation of WNT signalling via endocytosis of the Frizzled–LRP complex (part b). However, when R-spondin is present (as in part a) and recruited to leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) and LGR5, RNF43 and ZNRF3 interact with R-spondin, resulting in membrane clearance of the complex and the potentiation of WNT signalling. WNT signalling is important for proliferation and maintenance of potency as well as the differentiation of stem cells.
Figure 3
Figure 3. Modes of stem cell division
This figure depicts the modes of division — that is, asymmetric (part a) or symmetric (part b; either non-differentiative or differentiative) — in stem cells and illustrates how the orientation of the mitotic spindle in relation to the stem cell niche regulates the outcome of the division.
See this image and copyright information in PMC

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