WNT signalling events near the cell membrane and their pharmacological targeting for the treatment of cancer

Abstract

WNT signalling is an essential signalling pathway for all multicellular animals. Although first described more than 30 years ago, new components and regulators of the pathway are still being discovered. Considering its importance in both embryonic development and adult homeostasis, it is not surprising that this pathway is often deregulated in human diseases such as cancer. Recently, it became clear that in addition to cytoplasmic components such as β-catenin, other, membrane-bound or extracellular, components of the WNT pathway are also altered in cancer. This review gives an overview of the recent discoveries on WNT signalling events near the cell membrane. Furthermore, membrane-associated components of the WNT pathway, which are more accessible for therapeutic intervention, as well therapeutic approaches that already target those components will be discussed. In this way, we hope to stimulate the development of effective anti-cancer therapies that target this fascinating pathway. LINKED ARTICLESThis article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc Abbreviations APC, adenomatosis polyposis coli; CRD, cysteine-rich domain; DKK protein, Dickkopf protein; DVL, Dishevelled; FZD, Frizzled; GSK3, glycogen synthase kinase 3; LGR, leucine-rich repeat-containing GPCR; LRP, LDL-receptor related protein; RNF43, ring finger protein 43; sFRP, secreted Frizzled related protein; SOST, sclerostin; Swim, Secreted wingless interacting molecule; TCF, T-cell factor; TSPAN12, tetraspanin-12; wg, wingless; WIF, WNT inhibitory factor; Wise, WNT modulator in surface ectoderm, ZNRF3, zinc and ring finger 3 WNT signallingOriginally named Int-1, WNT 1 was identified as a preferential insertion site for the mouse mammary tumour virus in virally induced breast cancers (Nusse and Varmus, 1982). Shortly after, WNT1 was found to be the mammalian homologue of a Drosophila gene named wingless (wg) (Nüsslein-Volhard and Wieschaus, 1980). In wg mutant fly embryos, major embryonic defects including the absence of proper wing development were observed. Similar phenotypes were found in flies with defects in the genes encoding zestewhite (glycogen synthase kinase 3; GSK3), Dishevelled (DVL) and armadillo (β-catenin). Subsequently, epistasis experiments revealed that these genes encode the core proteins of a developmental signalling cascade (Siegfried et al., 1992;Noordermeer et al., 1994;Peifer et al., 1994), which was named the WNT signalling pathway, as an amalgam of wg and Int-1 (Cabrera et al., 1987). Around the same time, another protein, adenomatosis polyposis coli (APC), was found to interact with β-catenin (Rubinfeld et al., 1993;Su et al., 1993). As APC mutations had previously been associated with a hereditary predisposition for colon cancer (Kinzler et al., 1991;Nishisho et al., 1991), this was the first time that the WNT pathway was directly linked with human disease (Clevers an...

Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy

“…A great deal of work has been performed to uncover the intricacies of the signal transduction steps at the cell surface and the cytoplasm to better understand the normal and dysfunctional activity of Wnt signalling. Recent reviews published elsewhere and in this issue describe our current understanding of these steps in detail (Niehrs and Acebron, ; DeBruine et al, ; Driehuis and Clevers, ; Nusse and Clevers, ; van Kappel and Maurice, ; Zimmerli et al, ).…”

<em>Wnt/&beta;-Catenin</em> Signaling Pathway Governs a Full Program for Dopaminergic Neuron Survival, Neurorescue and Regeneration in the MPTP Mouse Model of Parkinson&rsquo;s Disease<strong> </strong>

“…This leads to changes in cell movement and polarity and to the antagonism of the β-catenin pathway, at multiple points Dkk1. Besides antagonists, Wnt signaling pathway is also activated and regulated by some secreted proteins acting as agonists, for example, R-spondin (Rspo) [38][39][40][41].…”

“…By contrast, pivotal PD proteins encoded by genes whose mutations have been linked to PD, were demonstrated to impact on canonical Wnt/β-catenin signaling [65][66][67] and to inhibit human induced pluripotent stem cells (iPSCs)' ability to differentiate into DAergic neurons [68], whereas pharmacological Wnt activation restored their developmental potential [68]. With the emerging role of micro-RNA (miRNA) regulatoy functions on major pathways involved in mDAergic neurodegeneration in PD [69][70][71], patient-specific dysregulation of mRNA/miRNAs expression is being revealed in PD [72], with an expected impact on Wnt signaling [41,[72][73][74].…”

WNT signalling: mechanisms and therapeutic opportunities

“…The review by Driehuis and Clevers () provides a broad introduction to the field of WNT signalling focusing on the signalling components and regulators at the cell membrane, with special emphasis on receptor complex formation and ubiquitination‐mediated internalization. Another level of receptor complex dynamics, complex composition and assembly of the WNT/β‐catenin signalosome is taken up by Zachary DeBruine, a PhD student from the Karsten Melcher laboratory at van Andel Institute, who presented a talk selected from an abstract submitted at the WNT meeting (DeBruine et al ., ).…”