Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction

Wang, Sheng; Yin, Jie; Chen, Duozhi; Nie, Fan; Song, Xiaomin; Cong, Fengyu; Miao, Haofei; Jing, Chang-Bin; Ma, Wenjing; Wang, Lei; Xie, Sichun; Li, Chen; Zeng, Rong; Pan, Weijun; Hao, Xiao‐Jiang; Li, Lin

doi:10.1038/nchembio.1309

Cited by 79 publications

(84 citation statements)

References 50 publications

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“…5L). Previously, we identified Caprin2 as a positive regulator in Wnt/␤-catenin signaling by promoting axin-LRP5 interaction (37), and more recently, a small molecule, HLY78, was found to activate Wnt/␤-catenin signaling through modulating the interaction between axin and LRP6 (38). Here, we demonstrate that protein ubiquitination provides an alternative way to regulate axin-LRP5/6 interaction.…”

Section: Discussionmentioning

confidence: 51%

Smurf1-Mediated Lys29-Linked Nonproteolytic Polyubiquitination of Axin Negatively Regulates Wnt/β-Catenin Signaling

Fang

et al. 2013

Molecular and Cellular Biology

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Ubiquitination plays important and diverse roles in modulating protein functions. As a C2-WW-HECT-type ubiquitin ligase, Smad ubiquitination regulatory factor 1 (Smurf1) commonly serves to regulate ubiquitin-dependent protein degradation in a number of signaling pathways. Here, we report a novel function of Smurf1 in regulating Wnt/␤-catenin signaling through targeting axin for nonproteolytic ubiquitination. Our data unambiguously demonstrate that Smurf1 ubiquitinates axin through Lys 29 (K29)-linked polyubiquitin chains. Unexpectedly, Smurf1-mediated axin ubiquitination does not lead to its degradation but instead disrupts its interaction with the Wnt coreceptors LRP5/6, which subsequently attenuates Wnt-stimulated LRP6 phosphorylation and represses Wnt/␤-catenin signaling. The inhibitory function of Smurf1 on Wnt/␤-catenin signaling is further evidenced by analysis with Smurf1 knockout murine embryonic fibroblasts. We next identified K789 and K821 in axin as the ubiquitination sites by Smurf1. Consistently, Smurf1 could neither disrupt the interaction of an axin K789/821R double mutant with LRP5/6 nor attenuate the phosphorylation of LRP6 in axin K789/821R -expressing cells. Collectively, our studies uncover Smurf1 as a new regulator for the Wnt/␤-catenin signaling pathway via modulating the activity of axin.

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Section: Discussionmentioning

confidence: 51%

Smurf1-Mediated Lys29-Linked Nonproteolytic Polyubiquitination of Axin Negatively Regulates Wnt/β-Catenin Signaling

Fang

et al. 2013

Molecular and Cellular Biology

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“…Kim et al ., [65] proposed that without Wnt, Axin is associated with and phosphorylated by GSK3β, which is present in an activated (“open”) conformation for β-catenin binding and is poised for engagement of LRP6. In the presence of Wnt, LRP6 undergoes Fz /DVL-dependent phosphorylation and recruits active Axin from the “destruction complex” to form the signaling queue, in which GSK3β bound to Axin is inhibited by the phospho-LRP6 [73–76], consequently leading to inhibition of β-catenin phosphorylation which tips the balance toward Axin dephosphorylation by PP1 phosphatase. The dephosphorylated Axin form adopts an inactivated (“closed”) conformation through intramolecular auto-inhibition and becomes incompetent for association with β-catenin or phospho-LRP6, leading to the disassembly of destruction and signaling complexes.…”

Section: Discussionmentioning

confidence: 99%

Low-density lipoprotein receptor-related protein 6 is a novel coreceptor of protease-activated receptor-2 in the dynamics of cancer-associated β-catenin stabilization

et al. 2017

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Protease-activated receptor-2 (PAR2) plays a central role in cancer; however, the molecular machinery of PAR2-instigated tumors remains to be elucidated. We show that PAR2 is a potent inducer of β-catenin stabilization, a core process in cancer biology, leading to its transcriptional activity. Novel association of low-density lipoprotein-related protein 6 (LRP6), a known coreceptor of Frizzleds (Fz), with PAR2 takes place following PAR2 activation. The association between PAR2 and LRP6 was demonstrated employing co-immunoprecipitation, bioluminescence resonance energy transfer (BRET), and confocal microscopy analysis. The association was further supported by ZDOCK protein-protein server. PAR2-LRP6 interaction promotes rapid phosphorylation of LRP6, which results in the recruitment of Axin. Confocal microscopy of PAR2-driven mammary gland tumors in vivo, as well as in vitro confirms the association between PAR2 and LRP6. Indeed, shRNA silencing of LRP6 potently inhibits PAR2-induced β-catenin stabilization, demonstrating its critical role in the induced path. We have previously shown a novel link between protease-activated receptor-1 (PAR1) and β-catenin stabilization, both in a transgenic (tg) mouse model with overexpression of human PAR1 (hPar1) in the mammary glands, and in cancer epithelial cell lines. Unlike in PAR1-Gα13 axis, both Gα12 and Gα13 are equally involved in PAR2-induced β-catenin stabilization. Disheveled (DVL) is translocated to the cell nucleus through the DVL-PDZ domain. Collectively, our data demonstrate a novel PAR2-LRP6-Axin interaction as a key axis of PAR2-induced β-catenin stabilization in cancer. This newly described axis enhances our understanding of cancer biology, and opens new avenues for future development of anti-cancer therapies.

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“…Dvl also mediates various β-catenin-independent, non-canonical Wnt signaling pathways, including the Rho/JNK-mediated planar cell polarity (PCP) pathway that controls actin cytoskeleton 7 . Due to its critical involvement in cancer and other diseases, the canonical Wnt pathway has been a major target for drug development 8-12 . More recently, Dvl has emerged as an attractive target for therapeutic intervention 13,14 .…”

Section: Introductionmentioning

confidence: 99%

Cholesterol selectively activates canonical Wnt signalling over non-canonical Wnt signalling

et al. 2014

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Wnt proteins control diverse biological processes through β-catenin-dependent canonical signaling and β-catenin-independent non-canonical signaling. The mechanisms by which these signaling pathways are differentially triggered and controlled are not fully understood. Dishevelled (Dvl) is a scaffold protein that serves as the branch point of these pathways. Here, we show that cholesterol selectively activates canonical Wnt signaling over non-canonical signaling under physiological conditions by specifically facilitating the membrane recruitment of the PDZ domain of Dvl and its interaction with other proteins. Single molecule imaging analysis shows that cholesterol is enriched around the Wnt-activated Frizzled and low-density lipoprotein receptor-related protein 5/6 receptors and plays an essential role for Dvl-mediated formation and maintenance of the canonical Wnt signaling complex. Collectively, our results suggest a new regulatory role of cholesterol in Wnt signaling and a potential link between cellular cholesterol levels and the balance between canonical and non-canonical Wnt signaling activities.

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Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction

Cited by 79 publications

References 50 publications

Smurf1-Mediated Lys29-Linked Nonproteolytic Polyubiquitination of Axin Negatively Regulates Wnt/β-Catenin Signaling

Smurf1-Mediated Lys29-Linked Nonproteolytic Polyubiquitination of Axin Negatively Regulates Wnt/β-Catenin Signaling

Low-density lipoprotein receptor-related protein 6 is a novel coreceptor of protease-activated receptor-2 in the dynamics of cancer-associated β-catenin stabilization

Cholesterol selectively activates canonical Wnt signalling over non-canonical Wnt signalling

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