Assembly and architecture of the Wnt/β‐catenin signalosome at the membrane

Abstract

Wnt/β-catenin signalling is initiated by a ternary Wnt-Frizzled (FZD)-LDL receptor-related protein (LRP) 5/6 binding event. The resulting conformational changes in the FZD and LRP5/6 receptors promote the assembly of an intracellular signalosome driven by Dishevelled and Axin co-polymerization. Recent evidence suggests that the FZD receptor and LRP5/6 participate in the assembly of this signalosome by forming regulatory scaffolds for stabilizing Dishevelled and Axin adapters. In this review, we focus on the contributions of Wnts and their receptors in the assembly of the signalosome. We present an emerging model, which unifies Wnt receptor oligomerization with intracellular signalosome formation, and then discuss how FZD receptors might be targeted to either disrupt or enhance their capacity as a dynamic sensor of Wnt binding. 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 IntroductionWingless/int1 (Wnt) signal activation is tightly controlled by a dynamic signalosome consisting of Class Frizzled GPCRs (FZDs), LDL receptor-related protein (LRP) 5/6 coreceptors and Dishevelled and Axin adapters (Cong et al., 2004;Kaykas et al., 2004;Bilic et al., 2007;Gammons et al., 2016a). In this review, we discuss emerging evidence for a model of FZD and LRP5/6 co-oligomerization. In this model, oligomerization of the Wnt signalling complex is facilitated by domains with weak homo-oligomerization propensities such as the FZD cysteine-rich domain (CRD), the LRP5/6 β-propeller (βP) domains, and the Dishevelled EGL-10 and pleckstrin (DEP) and Dishevelled and Axin (DIX) domains (Dann et al., 2001;Gammons et al., 2016b). In the absence of Wnt, inactive complexes of FZD, LRP5/6 and DVL pose as static sensors for Wnt binding (Chen et al., 2014) ( Figure 1A). When Wnt binds FZD receptors and LRP5/6, the FZD receptor and LRP5/6 complexes are activated and oligomerize to create an extensive scaffold for Dishevelled stabilization and interaction with LRP5/6 (Bilic et al., 2007) ( Figure 1B). Dishevelled then co-polymerizes with Axin through shared DIX domains to form a trap which sequesters the β-catenin destruction complex (Schwarz-Romond et al., 2007;Fiedler et al., 2011).Consequentially, β-catenin translocates to the nucleus where it works in concert with Wnt transcription factors to turn on Wnt target genes (van de Wetering et al., 1991). Wnt family ligands are FZD-specific, highly conserved and often determine developmental patterning and cell fate (van de Wetering et al., 1997). Many of these physiological consequences are the result of Wnt/β-catenin signalling which involves the assembly of an intracellular Dishevelled/Axin signalosome (Cong et al., 2004; SchwarzRomond et al., 2007). Unlike norrin, an atypical FZD 4 / LRP5 agonist, all 19 human Wnts share a highly conserved two-domain structure which enables it to attach the FZD receptor CRD and bin...

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, ).…”

Wnt Regulation: Exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex

“…Here we address this issue.A second set of outstanding questions concern the mechanisms by which Wnt signaling down-regulates βcat destruction. Wnt signaling is initiated when Wnt ligands interact with complex multi-protein receptors, comprised of Frizzled family members plus LRP5/6 (reviewed in (DeBruine et al, 2017;Nusse and Clevers, 2017). This receptor complex recruits the destruction complex to the plasma membrane, via interaction of Axin with the phosphorylated LRP5/6 tail and with the Wnt effector Disheveled (Dvl in mammals/Dsh in Drosophila).This leads to downregulation of the destruction complex, reducing the rate of βcat destruction.…”

Functional dissection of the N-terminal extracellular domains of Frizzled 6 reveals their roles for receptor localization and Dishevelled recruitment

“…FZDs, the focus of this study, bind WNT proteins with their extracellular cysteine-rich domain (CRD) to initiate a complex network of WNT signaling pathways (2). The CRD is seen as the orthosteric binding site for WNTs and is functionally implicated in receptor dimerization and signal initiation (3)(4)(5)(6). Structurally, the CRD is connected to the seven transmembrane (7TM) core of the receptor through a linker domain of variable length and low degree of conservation among the representatives of class F (5).…”

“…The CRD is seen as the orthosteric binding site for WNTs and is functionally implicated in receptor dimerization and signal initiation (3)(4)(5)(6). Structurally, the CRD is connected to the seven transmembrane (7TM) core of the receptor through a linker domain of variable length and low degree of conservation among the representatives of class F (5). A central intracellular interaction partner of FZDs is the scaffold protein Dishevelled (DVL), of which three isoforms exist in mammals (7,8).…”