Article Figures & Data
Figures
- Fig. 1.
Synthesis, posttranslational modification, and exporting of WNT proteins. After translation of WNT proteins, a palmitoleate group is attached by Porcupine in the endoplasmic reticulum (ER). This promotes the binding to Wntless (WLS), a chaperone protein that facilitates the migration of WNT through the Golgi complex. When WNT has reached the plasma membrane, it can either be secreted in exosomes or be attached to lipoproteins or Swim proteins; this is required to shield the large lipophilic moiety and increase the water solubility of the WNT protein. WNT can also attach to the plasma membrane of the producing cell by forming a complex with heparin sulfate proteoglycan (HSPG). Upon delivery of WNT to the plasma membrane, WLS is recycled via the retromer complex to the Golgi apparatus.
- Fig. 2.
Mechanisms of regulating WNT signaling activity. (A) In the absence of regulating mechanisms, WNT can bind to the FZD/LRP5/6 complex and activate signaling. (B) In the classic view, soluble frizzled-related proteins (sFRPs) can bind WNT and prevent its interaction with the receptor complex. However, sFRPs can modulate Wnt signaling in different ways, as described in the text (C). Adenomatous polyposis coli downregulated-1 (APCDD1) is a membrane-bound glycoprotein that can bind WNT and prevent its interaction with the receptor complex. (D) WNT-inhibitory factor (WIF) is a secreted protein shown to attenuate WNT signaling by binding the protein that prevents the association with the receptor complex. (E) Tiki is a transmembrane protein with proteolytic activity, cleaving an peptide of 8–20 amino acids from the N-terminal part of WNT proteins. This causes the formation of oligomers of WNT proteins that are inactive in signal transduction. (F) Notum is a carboxylesterase capable of removing the palmitoleic acid residue from WNT, making the protein biologically inactive.
- Fig. 3.
Regulation of the amount of FZD protein on the plasma membrane. (A) Association of the transmembrane E3 ligases RNF43 and/or ZNRF3 with the FZD receptor complex induces its ubiquitination and leads to internalization of the receptor complex, making it unavailable for stimulation with WNT. (B) R-spondin is capable of redirecting the E3 ligases toward LGR4 or -5, inducing the internalization of this transmembrane protein rather than the FZD/LRP5/6 complex. This effectively leaves more FZD receptors at the plasma membrane, available for stimulation with WNT proteins.
- Fig. 4.
Schematic representation of the WNT/β-catenin signal transduction pathway. (Left) In the “Off” state, β-catenin is bound in a so-called β-catenin destruction complex containing glycogen synthase kinase 3β (GSK3β), axin, adenomatous polyposis coli (APC) and casein kinase-1 (CK-1). The kinases in this complex phosphorylate β-catenin, thereby targeting it for degradation by the ubiquitin proteasome system. (Right) In the “On” state, the receptor complex consisting of frizzled and LRP5/6 bind WNT, which recruits the disheveled (DVL) protein to the plasma membrane. Subsequently, several components of the β-catenin destruction complex are recruited to the membrane, which prevents the phosphorylation of β-catenin. Therefore, this protein can now accumulate in the cytoplasm and translocate to the nucleus to associate with transcription factors and stimulate the transcription of WNT target genes such as cycline-D1, c-myc, and axin2.
- Fig. 5.
Schematic representation of the planar cell polarity pathway. In this pathways two receptor complexes are formed at the opposite sides of a cell: On one side, frizzled forms a complex with Flamingo/Celsr, disheveled (Dvl), and Diego/Diversin, whereas the other side the complex consists of Flamingo/Celsr, Van Gogh/Vang, and Prickle. The extracellular parts of these complexes interact, thereby controlling the cellular polarization via activation of JNK/p38 MAPK, small GTPase and Rho-associated kinase (ROCK) signaling. Although the role of Wnt in this signal transduction cascade is only partially understood, this protein may interfere with the Vangl1-FZD interaction. This could subsequently disturb the balance between the signaling of the Vang1/Prickle/Celsr complex and the FZD/DVL/Diego/Celsr complex.
- Fig. 6.
The role of WNT signaling in sprouting angiogenesis. In this process, tip cells provide directional cues to the sprout cells that can proliferate and initiate the formation of a new vessel. WNT signaling can contribute to the proliferation and tube formation of the stalk cells. The effect of WNT signaling on the tip cells is likely to be indirect via the expression of delta-like ligand-4 (Dll4) in the stalk cells, which activates Notch signaling in the tip cells.
- Fig. 7.
WNT signaling in atherosclerosis. The contribution of WNT signaling to the development and progression of atherosclerosis is described at the intima and media levels with a central role for the contribution of monocytes/macrophages (section VII.A). ABCA1, ATP-binding cassette transporter 1; agLDL, aggregated LDL; ox-LDL, oxidized LDL; MCP-1, monocyte chemotactic protein-1.
- Fig. 8.
Different sites of pharmacological intervention in WNT signaling. Details are provided in section XI. (1) Targeting of FZD proteins (e.g., vantictumab or UM206); (2) WNT scavengers (e.g., ipafricept); (3) Porcupine inhibitors (e.g., LGK974 or IWP-2); (4) Glycogen synthase kinase-3β (GSK3β) inhibitors (e.g., LiCl, valproic acid, 6-BIO); (5) Casein kinase-1 (CK1) inhibitors (e.g., pyrvinium); (6) Tankyrase inhibitors (e.g., XAV939, IWR-1); (7) Inhibitors of the interaction between β-catenin and the TCF transcription factors (e.g., ICRT3, -5, and -14, nonsteroid anti-inflammatory drugs); (8, 9, 10) Inhibitors of the interaction of the transcription complex with the cofactors p300, CBP, and BCL9 (e.g., windorphen, ICG-001, and SAH-BCL9).
Tables
Gene Pathway Role Reference WNT1 β-catenin mediated Cardiac neural crest cell development and outflow tract development Brault et al. (2001) WNT2B non-β-catenin mediated Inhibition of cardiac progenitor cells Wang et al. (2007) WNT3A β-catenin mediated Mesoderm formation Liu et al. (1999) Inhibition of cardiac progenitor cells Marvin et al. (2001) WNT5A non-β-catenin mediated Cardiomyocyte differentiation and outflow tract septation Schleiffarth et al. (2007) WNT7A non-β-catenin mediated Conduction system development Bond et al. (2003) WNT9B β-catenin mediated Epicardium development and coronary artery formation Zamora et al. (2007) WNT11 non-β-catenin mediated Cardiomyocyte differentiation Pandur et al. (2002) Outflow tract septation Zhou et al. (2007) Conduction system development Bond et al. (2003) Intervention Use Proposed Target Effect Affinity Reference Porcn genetic deletion In vivo (mice) Porcn gene Inhibition of WNT3A secretion n/a Barrott et al. (2011) IWP-1 In vitro PORCN protein Inhibition of WNT secretion (WNT1, -2, and -3A?) IC50: 58 nM Chen et al. (2009a) IWP-2 In vitro PORCN protein Inhibition of WNT-1, -2, −3a secretion IC50: 27 nM Chen et al. (2009a) IWP-3 In vitro PORCN protein Inhibition of WNT secretion (WNT1, -2, and -3A?) IC50: 40 nM Chen et al. (2009a) IWP-4 In vitro PORCN protein Inhibition of WNT secretion (WNT1, -2, and -3A?) IC50: 25 nM Chen et al. (2009a) IWP-L6 In vitro PORCN protein Inhibition of WNT secretion IC50: 0.5 nM Wang et al. (2013b) LGK974 In vitro PORCN protein Inhibition of WNT1, -2, -3, -3A, −6, -7A, and -9A secretion IC50: 0.3–0.4 nM (depending on the cell assay) Liu et al. (2013) ETC-159 In vitro PORCN protein Inhibition of WNT1, -2, -3A, -6, -7B, −8A, -9A, -9B, and -10B secretion IC50: 2.9 nM β-catenin reporter assay) Madan et al. (2016a) IC50: 18.1 nM (mouse PORCN inhibition) WNT-C59 In vitro and in vivo (mice) PORCN protein Inhibition of WNT1, -2, -3A, -6, -7B, −8A, -9A, -9B, and -10B secretion IC50: 74 pM (WNT-3a-mediated Proffitt et al. (2013) TOPFLASH assay) Compound 53 In vitro PORCN protein Inhibition of WNT-3a secretion IC50: 0.5 nM Xu et al. (2016) 4,4-DiOMEA In vitro PORCN protein? Inhibition of WNT-16 secretion IC50: 7.6 ± 1.5 nM Ramirez de Molina et al. (2015) Intervention Use Proposed Target Effect Affinity Reference OMP-18R5 (mAb) In vitro and in vivo (mice) FZD1, FZD2, FZD5, FZD7, FZD8 Inhibition of WNT-FZD interaction n/a Gurney et al. (2012) OTSA101 (mAb) + Yttrium 90 In vitro, in vivo (mice) and CT FZD10 Inhibition of WNT-FZD interaction n/a Fukukawa et al. (2008) TT641 (pAb) In vitro and in vivo (mice) FZD10 Inhibition of WNT-FZD interaction n/a Nagayama et al. (2005) 1.99.15 (mAb) In vitro and in vivo (mice) FZD4 Inhibition of WNT-FZD interaction n/a Paes et al. (2011) pAb against FZD5 In vitro FZD5 Inhibition of WNT-FZD interaction n/a Sen et al. (2001) Ab against FZD7 In vitro and in vivo (chick embryo) FZD7 Inhibition of WNT-FZD interaction n/a Pode-Shakked et al. (2011) OMP-54F28 fusion protein In vitro, in vivo (mice) and CT FZD8-interacting WNT ligands Inhibition of WNT-FZD interaction n/a Le et al. (2015), Fischer et al. (2015) Jimeno et al. (2014) UM206 In vitro and in vivo (mice) FZD1 and FZD2 Inhibition of WNT-FZD interaction IC50: 2.10 nM for rFZD1; Laeremans et al. (2011) IC50: 0.0169 nM for rFZD2 Uitterdijk et al. (2016) Foxy5 + FZD5 receptor-blocking Ab In vitro and in vivo (mice) FZD5 Mimicking of WNT5A (effect independent of β-catenin) n/a Safholm et al. (2006)Safholm et al. (2008) Box5 In vitro FZD5 (?) Blockade of WNT5A signaling n/a Jenei et al. (2009) 3235–0367 In vitro FZD8 CRD Inhibition of WNT-FZD interaction IC50: 7.1 μM Lee et al. (2015) 1094–0205 In vitro FZD8 CRD Inhibition of WNT-FZD interaction IC50: 5 μM Lee et al. (2015) 2124–0331 In vitro FZD8 CRD Inhibition of WNT-FZD interaction IC50: 10.4 μM Lee et al. (2015) NSC36784 In vitro FZD8 CRD Inhibition of WNT-FZD interaction IC50: 6.5 μM Lee et al. (2015) NSC654259 In vitro FZD8 CRD Inhibition of WNT-FZD interaction IC50: 5.7 μM Lee et al. (2015) Niclosamide In vitro FZD1 (internalization) Inhibition of WNT-FZD interaction IC50: 0.5 μM Chen et al. (2009b) In vitro LRP6 LRP6 degradation IC50: 0.33–0.75 μM Lu et al. (2011b) (depending on the cell line) Curcumin In vitro FZD1 Inhibition of WNT-FZD interaction (?) n/a Yan et al. (2005) In vitro WNT3A; LRP6 Inhibition of WNT-FZD interaction (?) n/a Zheng et al. (2017) In vitro WNT10B; FZD2; LRP5 Enhancement of WNT-FZD interaction n/a Ahn et al. (2010) anti-Sclerostin Ab In vitro Sclerostin binding Prevention of Sclerostin-mediated disruption n/a van Dinther et al. (2013) to LRP5/6 of LRP5/6-FZD complex formation Salinomycin In vitro LRP6 (?) Inhibition of WNT1/FZD5/LRP6 and IC50: 163 nM (WNT-1) Lu et al. (2011) WNT3/FZD5/LRP6 complexes In vitro LRP6 Inhibition of WNT/FZD/LRP6 complex (?) n/a Lu and Li (2014) Leptin In vivo (mice) LRP6; WNT4 and WNT7 (?); Enhancement of WNT4/FZD/LRP6 n/a Benzler et al. (2013) GSK-3β and WNT7A/FZD/LRP6 complexes Silibinin In vitro LRP6 Inhibition of WNT3A/FZD/LRP6 complex IC50: 34–122 μM (depending on the cell line) Lu et al. (2012) anti-LRP6 Abs In vitro LRP6 Inhibition of WNT1 and WNT3A-mediated cascade n/a Ettenberg et al. (2010) (WNT/FZD/LRP6 complex?) In vitro LRP6 Inhibition or enhancement of WNT1/2/2B/4/6/7A/7B/8A/9B/10A/10B-mediated n/a Gong et al. (2010) cascade (WNT/FZD/LRP6 complex?) 28aa peptide In vitro andin vivo (mice) LRP5/6 Mimicking of LRP5/6-domain → Enhancement of n/a Hay et al. (2012) WNT signaling (via N-cadherin) DKK1 and DKK2 In vivo (Xenopus embryos) LRP6 Inhibition of WNT signaling n/a Mao et al. (2001) anti-DKK1 Ab In vitro and in vivo (mice) DKK1 Neutralization of DKK1 → Enhancement of WNT signaling n/a Sato et al. (2010b) BHQ880 mAb In vitro, in vivo (mice) and CT DKK1 Neutralization of DKK1 → Enhancement of WNT signaling n/a Fulciniti et al. (2009) Iyer et al. (2014) DKK1 vaccine In vivo (mice) DKK1 Enhancement of DKK1 levels → Inhibition of WNT signaling n/a Qian et al. (2012) Iminooxothiazolidines (Compounds 1–34) In vitro sFRP1 Inhibition of sFRP1 → Enhancement of WNT signaling EC50: 7.2 μM (Compound 1) Shi et al. (2009) WAY-316606 In vitro sFRP1 Inhibition of sFRP1 → Enhancement of WNT signaling IC50: 0.5 μM Bodine et al. (2009) EC50: 0.65 μM Moore et al. (2010) N-substituted piperidinyl In vitro sFRP1 Inhibition of sFRP1 → Enhancement of WNT signaling IC50: 0.04–0.87 μM Moore et al. (2010) diphenylsulfonyl sulfonamides ED50: 0.07–1.9 μM Intervention Use Proposed target Effect Affinity Reference 1. Interventions Targeting Disheveled 3289–8625 In vitro and in vivo (Xenopus embryos and mice) DVL PDZ Blockade of DVL → Inhibition of WNT signaling IC50: 10.5 μM Grandy et al. (2009) NSC668036 In silico and in vivo (Xenopys embryos) DVL PDZ Blockade of DVL → Inhibition of WNT signaling n/a Shan et al. (2005) J01-017a In silico DVL PDZ Blockade of DVL → Inhibition of WNT signaling n/a Shan et al. (2012) FJ9 In vitro and in vivo (mice) DVL PDZ FZD7-DVL PDZ interaction disruption → Inhibition of WNT signaling n/a Fujii et al. (2007) PolyR-DBM Ex vivo and in vitro DVL-CXXC5 FZD7-DVL PDZ interaction disruption → Inhibition of WNT signaling n/a Kim et al. (2015) KY-02327 In silico, in vitro, ex vivo, in vivo (mice) DVL-CXXC5 FZD7-DVL PDZ interaction disruption → Inhibition of WNT signaling IC50: 3.1 μM Kim et al. (2016) KY-02061 In silico, in vitro, ex vivo, in vivo (mice) DVL-CXXC5 FZD7-DVL PDZ interaction disruption → Inhibition of WNT signaling IC50: 24 μM Kim et al. (2016) pen-N3 In silico and in vitro DVL PDZ Blockade of DVL → Inhibition of WNT signaling IC50: 11 ± 4 μM Zhang et al. (2009b) 2. Interventions Targeting Axin XAV939 In vitro and in vivo (mice) axin Induction of protein levels and stabilization of axin → Enhancement of IC50: 0.114–2.194 μM (PARP1/2); Huang et al. (2009), Wang et al. (2014a) axin-GSK3β complex formation → Inhibition of Wnt Signaling IC50: 0.004–0.011 μM (TNKS1/2) IWR-1 and IWR-2 In vitro and in vivo (zebrafish and mice) axin Induction of protein levels and stabilization of axin → Enhancement of IC50 IWR-1: 0.18 μM; Chen et al. (2009), Wang et al. (2014a) axin-GSK3β complex formation → Inhibition of Wnt Signaling IC50 IWR-2: 0.23 μM XAV939 + 5-FU or cisplatin In vitro axin Induction of protein levels and stabilization of axin → Enhancement of n/a Wu et al. (2016b) axin-GSK3β complex formation → Inhibition of Wnt Signaling XAV939 + ICAT + niclosamide In vitro axin; β-catenin/ Stabilization of axin (XAV939), β-catenin/p300 complex inhibition (ICAT), n/a Ono et al. (2014) p300 complex; FZD1 FZD1 internalization (niclosamide) → Inhibition of Wnt Signaling E7449 In vitro and in vivo (mice) axin/PARPs TNKS proteins inhibition → Stabilization of axin → Inhibition of Wnt signaling IC50 PARP1/2: 1–2 nM, IC50 TNKS1/2: 50–120 nM McGonigle et al. (2015) WXL-8 In vitro and in vivo (mice) axin/TNKSs TNKS proteins inhibition → Stabilization of axin → Inhibition of Wnt signaling IC50: 9.1 nM (TNKS1) Ma et al. (2015) JW67, JW74 and JW55 In vitro and in vivo (Xenopus embryos and mice) axin TNKS proteins inhibition → Induction of protein levels and stabilization of axin → IC50 JW67: 1.17 mM; IC50 JW64: 790 nM; Waaler et al. (2011), (2012) Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signaling IC50 JW55: 470 nM Compounds 13 and 14 In silico and in vitro axin/TNKSs TNKS proteins inhibition → Stabilization of axin → Inhibition of Wnt signaling IC50 = 2 nM (for TNKs2) Nathubhai et al. (2017) WIKI4 In vitro axin/TNKSs TNKS proteins inhibition → Halting of axin ubiquitination → IC50: 15 nM (TNKS2) James et al. (2012) Stabilization of axin → Inhibition of WNT signaling G007-LK In vitro and in vivo (mice) axin/TNKSs TNKS proteins inhibition → Stabilization of axin → Inhibition of WNT signaling IC50: 0.08 μM Lau et al. (2013) AZ1366 + EGFR-inhibitor In vitro and in vivo (mice) axin/TNKSs TNKS proteins inhibition → Stabilization of axin → Inhibition of WNT signaling n/a Scarborough et al. (2017) AZ1366 + irinotecanin In vitro and in vivo (mice) axin/TNKSs TNKS proteins inhibition → axin induction → n/a Quackenbush et al. (2016) IWRs (1-5) In vitro and in vivo (zebrafish) axin/TNKSs TNKS proteins inhibition → Induction of protein levels and stabilization of axin → IC50: 0.18–2.0 μM Chen et al. (2009) Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signaling NVP-TNKS656 In silico and in vitro axin/TNKSs TNKS proteins inhibition → Induction of protein levels and stabilization of axin → IC50: 0.006 μM (TNKS2) Shultz et al. (2013) Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signaling Compounds 9 and 25 In silico and in vitro axin/TNKSs TNKS proteins inhibition → Induction of protein levels and stabilization of axin → IC50: <0.003 μM (compound 9:) Johannes et al. (2015) Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signaling IC50: 0.005 μM (Wnt cell) (compound 25) SEN461 In vitro and in vivo (Xenopus embryos and mice) axin (not via TNKs?) Induction of protein levels and stabilization of axin → Enhancement of axin-GSK3β IC50: 18 μM (TNKS1); IC50: 2.9 μM (TNKS2); De Robertis et al. (2013) complex formation → Inhibition of Wnt Signaling IC50: 0.2–1.9 μM (Ca cell assays) De Robertis et al. (2014) Tigecycline (monotherapy or + paclitaxel) In vitro and in vivo (mice) axin1 Induction of protein levels and stabilization of axin1 → Enhancement of axin-GSK3β n/a Li et al. (2015) complex formation → Inhibition of Wnt Signaling SKL2001 In vitro axin Disruption of the axin/β-catenin interaction → Activation of Wnt signaling n/a Gwak et al. (2012) 3. Interventions Targeting CK1 Pyrvinium In vitro and in vivo (Xenopus embryo and mice) CK1 Induction of CK1α → Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signaling n/a Saraswati et al. (2010), Thorne et al. (2010) CKI-7 In vitro (Xenopus embryos and C. elegans) CK1/DVL Inhibition of CK and DVL → Inhibition of Wnt Signaling n/a Peters et al. (1999) IC261 In vitro CK1 Targeting of CK1ε → Inhibition of Wnt Signaling IC50: 0.5–86 μM (depending on cell line treated) Kim et al. (2010b) SB203580 In vitro CK1 Targeting of CK1δ/ε → Inhibition of Wnt Signaling ? Laco et al. (2015) SR-3029 In vitro and in vivo (mice) CK1 Targeting of CK1δ → Inhibition of Wnt Signaling n/a Rosenberg et al. (2015) 4. Interventions Activating GSK3β Curcumin In vitro GSK3β Akt inhibits p-GSK3β → activation of GSK3β → Enhancement of destruction complex → Inhibition of Wnt Signaling IC50: 25 mM (after 24 hours treatment) and 18.4 mM (after 48 hours treatment) Choi et al. (2010) 9-Hydroxycanthin-6-one In vitro and in vivo (zebrafish embryos) GSK3β Induction of GSK3β → Inhibition of Wnt Signaling (without involvement of CK) IC50: 36.7 - > 40 μM (depending on cell line) Ohishi et al. (2015) All-trans retinoic acid (ATRA) In vitro GSK3β Induction of GSK3β → Inhibition of Wnt Signaling n/a Zhu et al. (2015) S-ibuprofen In vitro GSK3β Induction of p-GSK3β → Inhibition of Wnt Signaling (NF-κB also involved) n/a Greenspan et al. (2011) 5. Interventions Inhibiting GSK3β Lithium In vitro GSK3β (and β-catenin) Inhibition of GSK3β (+ up-regulation of β-catenin) → Activation of Wnt Signaling n/a Wexler et al. (2008) Valproic acid In vitro GSK3β Inhibition of GSK3β → Activation of Wnt Signaling n/a Chen et al. (1999) 6-bromoindirubin-3′-oxime (BIO) In vitro and in vivo (mice) GSK3β Competitive inhibition of GSK3β → Activation of Wnt Signaling n/a Kohler et al. (2014) In vitro (incl. stem cells) GSK3β Inhibition of GSK3β → Activation of Wnt Signaling n/a Sato et al. (2004), Wen et al. (2010), Tseng et al. (2006) IBU-PO In vitro GSK3β Induction of p-GSK3β → Inhibition of GSK3β → Activation of Wnt Signaling n/a Farias et al. (2005) Curcumin In vitro GSK3β (and axin) Inhibition of GSK3β (and axin) → Activation of Wnt Signaling n/a Ahn et al. (2010) SB-216763 and SB-415286 In vitro GSK3α/β Inhibition of GSK3β → Activation of Wnt Signaling ID50: 34 nM (SB-216763); IC50: 78 nM (SB-415286) Coghlan et al. (2000) Kenpaullone In vitro (stem and progenitor cells) GSK3 Inhibition of GSK3 → Activation of Wnt Signaling n/a Lange et al. (2011) CHIR 99021 In vitro (incl. embryonic stem cells) GSK3α/β Inhibition of GSK3β → Activation of Wnt Signaling IC50: 5 nM (GSK3β) Bennett et al. (2002), Ye et al. (2012), Hou et al. (2013) Naujok et al. (2014) CG0009 In vitro GSK3β Induction of Ser9 p-GSK3β and inhibition of Tyr215 p-GSK3β → Inhibition of GSK3β →Activation of Wnt Signaling IC50: 0.49–>100 μM (depending on cell type in the assay) Kim et al. (2013) L803-mts In vitro and in vivo (mice) GSK3 Inhibition of GSK3 → Activation of Wnt Signaling IC50: 40 μM Plotkin et al. (2003), Kaidanovich-Beilin et al. (2004) Intervention Use Proposed target Effect Affinity Reference 1. Targeting of the TCF/LEF Transcription Factors iCRT3, iCRT5 and iCRT14 In vitro β-catenin-TCF/LEF complex Interference with the β-catenin/TCF interaction → Inhibition of WNT Signaling IC50: 8.2 nM (iCRT3); IC50: 18.7 nM (iCRT5); IC50: 40.3 nM (iCRT14) - in STF16 luciferase assay Gonsalves et al. (2011), Griffiths et al. (2015) Thiazole and oxazole In vitro β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling n/a Narayanan et al. (2012) 15-oxospiramilactone (NC043) In vitro β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling IC50: 0.9–6.9 μM (depending on the cell type) Wang et al. (2011b) Henryin In vitro β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling IC50: 0.6 ± 0.02 μM (ST-luciferase assay) Li et al. (2013c) 11α,12α-epoxyleukamenin E (EPLE) In vitro β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling n/a Ye et al. (2015) LF3 In silico, in vitro and in vivo (mice) β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling IC50: 2.4–4.0 mM (HeLa cells); IC50: 22.2 ± 4.9 mM (HEK293 TOPFlash assay) Fang et al. (2016) BC-21 In silico and in vitro β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling IC50: 5 μM (β-catenin-TCF4 inhibition assay) Tian et al. (2012) BC-23 (monotherapy or with radiation therapy) In silico and in vitro β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling IC50: 5 μM (β-catenin-TCF4 inhibition assay) Zhang et al. (2016a) PNU-74654 In vitro β-catenin-TCF/LEF complex Interference with the β-catenin/TCF interaction → Inhibition of WNT Signaling IC50: 117.2–5026.0 μM (depending on time and cell line used in the assay) Leal et al. (2015) PKF115-584 In vitro and in vivo (Xenopus embryos) In vitro and in vivo (mice) β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction, TCF binding with DNA, β-catenin/APC complex formation and antagonism of exogenous β-catenin → Inhibition of WNT Signaling IC50: 3.2 μM (β-catenin - TCF4 inhibition assay) IC50: 0.31–2.05 μM (sphere forming assay, range depending on cell type) Lepourcelet et al. (2004), Hallett et al. (2012) CGP049090 In vitro and in vivo (Xenopus embryos) β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction, TCF binding with DNA, β-catenin/APC complex formation and antagonism of exogenous β-catenin → Inhibition of WNT Signaling IC50: 8.7 μM (β-catenin-TCF4 inhibition assay) Lepourcelet et al. (2004) PKF222-815 In vitro and in vivo (Xenopus embryos) β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction and antagonism of exogenous β-catenin → Inhibition of WNT Signaling IC50: 4.1 μM (β-catenin - TCF4 inhibition assay) Lepourcelet et al. (2004) PKF118–310 In vitro and in vivo (mice) β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction and antagonism of exogenous β-catenin → Inhibition of WNT Signaling IC50: 0.8 μM (β-catenin-TCF4 inhibition assay) Lepourcelet et al. (2004) In vitro and in vivo (mice) IC50: 0.54–1.54 μM (sphere forming assay, range depending on cell type) Hallett et al. (2012) Daxx In vitro β-catenin-TCF/LEF complex Binding to TCF4 → Potentiation of β-catenin/TCF4-mediated transcriptional activation → Activation of WNT Signaling n/a Huang and Shih (2009) Quercetin In vitro β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling n/a Park et al. (2005) Isoquercitrin In vitro and in vivo (Xenopus embryos) β-catenin-TCF/LEF complex Interference with the β-catenin/TCF interaction → Inhibition of WNT Signaling n/a Amado et al. (2014) 6,7-dihydroxycoumarin (Aesculetin) In vitro and in vivo (Xenopus embryos and mice) β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling n/a Lee et al. (2013) Curcumin In vitro β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling n/a Jaiswal et al., 2002 In vitro β-catenin-TCF/LEF complex Decrease of TCF4, CBP and p300 protein levels → Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling n/a Teiten et al. (2011) Aspirin In vitro β-catenin-TCF gene transcription Suppression of gene transcription of β-catenin/TCF4 → Inhibition of WNT Signaling n/a Dihlmann et al. (2001) Indomethacin In vitro β-catenin-TCF gene transcription Suppression of gene transcription of β-catenin/TCF4 → Inhibition of WNT Signaling n/a Dihlmann et al. (2001) Celecoxib and 2,5-dimethyl-celecoxib In vivo (mice) β-catenin and TCF4 expression Suppression of β-catenin and TCF4 expression (not clear if the complex formation itself is affected) → Inhibition of TCF-mediated transcription → Inhibition of WNT Signaling n/a Fan et al. (2011), Egashira et al. (2017) Sulindac In vitro and in vivo (mice) TCF gene transcription Suppression of gene transcription of TCF → Inhibition of WNT Signaling IC50: 1.8–33.9 μM (for COX-1/2 and cGMP) Tinsley et al. (2010) In vitro β-catenin and TCF4 expression Suppression of gene transcription of TCF and β-catenin synthesis → Inhibition of WNT Signaling IC50: 75–83 μM (following 72 hour treatment of various human cancer cell lines) Li et al. (2013) ICAT In vitro and in vivo (Xenopus embryos) β-catenin-TCF/LEF complex Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling n/a Tago et al. (2000) In vitro β-catenin-TCF/LEF complex Interference with the β-catenin/TCF/LEF interaction → Inhibition of WNT Signaling n/a Daniels and Weis (2002) 2. Targeting of CBP ICG-001 (PRI-724) In vitro, in vivo (mice) and CT CBP Disruption of the β-catenin/CBP interaction → Inhibition of WNT Signaling IC50: 3 μM (TOPFlash assay) Emami et al. (2004), Henderson et al. (2010), El-Khoueiry et al. (2013), Sasaki et al. (2013) PMED-1 In silico and in vitro CBP Disruption of the β-catenin/CBP interaction → Inhibition of WNT Signaling IC50: 4.87–32 μM (depending on cell type in the TOPFlash assay) Delgado et al. (2014) Curcumin In vitro CBP Decrease of TCF4, CBP and p300 protein levels → Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling n/a Teiten et al. (2011) 3. Targeting of p300 ICAT In vitro p300 Inhibition of the β-catenin/Lef1/p300 interaction → Inhibition of WNT Signaling n/a Daniels and Weis (2002) ICAT-61 (helical domain of ICAT) In vitro p300 Disruption of the β-catenin/p300 interaction (but no interference with the binding of TCF/LEF) → Inhibition of WNT Signaling n/a Daniels and Weis (2002) Windorphen (WD) In vitro and in vivo (Zebrafish embryos) p300 Disruption of the β-catenin/p300 interaction → Inhibition of WNT Signaling IC50: 4.2 μM (p300); IC50: 1.5 μM (WNT3a-inducible TOPFlash assay) Hao et al. (2013) IQ1 In vitro and in vivo (mice) p300 Disruption of the β-catenin/p300 interaction → Amplification of the β-catenin/TCF4 interaction → Activation of WNT Signaling (paradox?) n/a Sasaki and Kahn (2014) Bisdemethoxycurcumin (BDMC) and demethoxycurcumin (DMC) In vitro p300 Downregulation of p300 (without effects on TCF4 or β-catenin levels) → Inhibition of WNT Signaling n/a Ryu et al. (2008) Curcumin In vitro p300 Decrease of TCF4, CBP and p300 protein levels → Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling n/a Teiten et al. (2011) 4. Targeting of BCL9 Carnosic acid (CA) In silico and in vitro β-catenin/BCL9 complex Interference with β-catenin/BCL9 interaction and degradation of β-catenin → Inhibition of WNT Signaling n/a de la Roche et al. (2012) In silico and in vitro β-catenin/BCL9 complex Interference with β-catenin/BCL9 interaction → Inhibition of WNT Signaling IC50: 8.7 ± 1.5–20 ± 0.18 μM (depending on cell line) Hoggard et al. (2015) LATS Large Tumor Suppressor (LATS) 2 In vitro and in vivo (mice) β-catenin/BCL9 complex Interference with β-catenin/BCL9 interaction → Inhibition of WNT Signaling n/a Li et al. (2013) Compound 11 In silico and in vitro β-catenin/BCL9 complex Interference with β-catenin/BCL9 interaction → Inhibition of WNT Signaling IC50: 22 ± 4.0–26 ± 6.6 μM (depending on cell line) Wisniewski et al. (2016) SAH-BCL9 In vitro and in vivo (mice) β-catenin/BCL9 complex Interference with β-catenin/BCL9 interaction → Inhibition of WNT Signaling IC50: 135–810 nM (depending on assay) Takada et al. (2012)
In this issue
WNT Signaling in Cardiovascular Disease
Jump to section
- Article
- Abstract
- I. Introduction
- II. The History of WNT Signaling
- III. Components of the Receptor Complex
- IV. Regulation of WNT Signaling
- V. Signal Transduction
- VI. WNT Signaling in Cardiac and Vascular Development
- VII. WNT Signaling in Vascular Disease
- VIII. WNT Signaling in Cardiac Disease
- IX. WNT Signaling in Stem Cells
- X. Crosstalk between WNT Signaling and Other Signal Transduction Pathways
- XI. Therapeutic Interventions
- XII. Future Perspectives
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
- Info & Metrics
- eLetters
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