Wnts grasp the WIF domain of Wnt Inhibitory Factor 1 at two distinct binding sites

Kerekes, Krisztina; Bányai, László; Patthy, László

doi:10.1016/j.febslet.2015.08.031

Cited by 15 publications

(14 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been shown that the antagonistic effect of WIF1 is mainly mediated by its WIF domain. In an attempt to map the Wnt binding sites in WIF domain, previous studies revealed the presence of an alkyl-binding site that is capable of interacting with essential lipid groups of Wnts [14–16]. Although WIF1 is expressed in different tissues, higher levels are reported in cartilage, lung, retina and brain [13, 17–20].…”

Section: Resultsmentioning

confidence: 99%

WIF1 prevents Wnt5A mediated LIMK/CFL phosphorylation and adherens junction disruption in human vascular endothelial cells

2017

View full text Add to dashboard Cite

BackgroundWnt5A is released by activated macrophages and elevated levels have been detected in sepsis patients with severe systemic inflammation. However, the signalling and functional effects of Wnt5A in the vascular endothelial cells (VEC) remained unclear. Recently, we showed that Wnt5A affects barrier function in human VEC through Ryk interaction. Wnt5A/Ryk signalling activates LIMK to inactivate the actin depolymerisation factor CFL by phosphorylation, promotes actin polymerisation and disrupts endothelial adherens junctions.FindingsHere, we investigate the antagonistic effect of the Ryk specific secreted Wnt antagonist Wnt inhibitory factor (WIF)-1 on Wnt5A-mediated activation/inactivation of LIMK/CFL, and adherens junction disruption in human VEC. In human coronary artery endothelial cells (HCAEC), treatment with Wnt5A enhanced the phosphorylation of LIMK and CFL that was significantly prevented by WIF1. The presence of WIF1 suppressed Wnt5A-mediated disruption of β-catenin and VE-cadherin adherens junctions in HCAEC, thereby preventing barrier dysfunction caused by Wnt5A.ConclusionWe conclude that WIF1 or molecules with similar properties could be potent tools for the prevention of vascular leakage due to Wnt5A-mediated actin cytoskeleton remodeling in diseases associated with systemic inflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12950-017-0157-4) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

WIF1 prevents Wnt5A mediated LIMK/CFL phosphorylation and adherens junction disruption in human vascular endothelial cells

2017

View full text Add to dashboard Cite

show abstract

“…Although it seems clear that ROR and RYK family members of the RTK superfamily play important roles in WNT signaling, their transmembrane signaling mechanisms are not yet understood (Green et al, 2014;Roy et al, 2018;Stricker et al, 2017). The presence of FZD-like CRD and WIF domains in the ECRs of ROR and RYK family receptors respectively initially suggested that WNT binding to these RTKs might resemble that seen for FZDs (Hirai et al, 2019;Janda et al, 2012) and proposed for WIF-1 (Kerekes et al, 2015;Malinauskas et al, 2011). Our crystal structures of CRD and WIF domains from Drosophila ROR and RYK/Drl family members, however, argue that they have their own unique characteristics, particularly with respect to the role of WNT-associated acyl chains in receptor engagement.…”

Section: Discussionmentioning

confidence: 99%

ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes

Shi

Mendrola

Sheetz

et al. 2021

Preprint

View full text Add to dashboard Cite

WNTs play key roles in development and disease, by binding both Frizzled (FZD) seven-pass transmembrane receptors and numerous co-receptors that include the ROR and RYK receptor tyrosine kinases (RTKs). We describe crystal structures and WNT-binding characteristics of extracellular regions from the Drosophila ROR and RYK orthologs Nrk (neurospecific receptor tyrosine kinase) and Derailed-2 (Drl-2). RORs bind WNTs though a FZD-related cysteine-rich domain (CRD), and RYKs through a WNT-inhibitory factor (WIF) domain. Our structures suggest that neither the Nrk CRD nor the Drl-2 WIF domain can accommodate the acyl chain typically attached to WNTs. The Nrk CRD contains a deeply buried bound fatty acid, unlikely to be exchangeable with a WNT acyl chain. The Drl-2 WIF domain lacks the lipid-binding site seen in WIF-1. We also show that DWnt-5, which regulates Drosophila ROR and RYK orthologs, lacks an acyl chain. Together with analysis of WNT/receptor interaction sites, these structures provide new insight into how WNTs recruit their RTK co-receptors into signaling complexes.

show abstract

“…Although the WIF domain has been shown to be sufficient for both WNT binding and inhibition of WNT signalling, recent data suggest that the EGF‐like domains enhance binding of WNT to WIF1 (Malinauskas et al ., ). Further work demonstrated that WIF1 interacts with WNT protein at multiple sites (Kerekes et al ., ). In a wide range of cancers, the Wif1 promoter region is methylated (Ai et al ., ; Kawamoto et al ., ; Veeck et al ., ), down‐regulating WIF1 expression.…”

Section: Wnt Signalling Enhancers or Inhibitorsmentioning

confidence: 97%

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

Driehuis

Clevers

2017

British J Pharmacology

View full text Add to dashboard Cite

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...

show abstract

Wnts grasp the WIF domain of Wnt Inhibitory Factor 1 at two distinct binding sites

Cited by 15 publications

References 43 publications

WIF1 prevents Wnt5A mediated LIMK/CFL phosphorylation and adherens junction disruption in human vascular endothelial cells

WIF1 prevents Wnt5A mediated LIMK/CFL phosphorylation and adherens junction disruption in human vascular endothelial cells

ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes

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

Contact Info

Product

Resources

About