Dishevelled: A masterful conductor of complex Wnt signals

Sharma, Monica; Castro‐Piedras, Isabel; Simmons, Glenn; Pruitt, Kevin

doi:10.1016/j.cellsig.2018.03.004

Cited by 166 publications

(160 citation statements)

References 184 publications

(181 reference statements)

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“…All known Wnt-induced pathways are transduced via seven transmembrane receptors There is a general agreement based on the genetic experiments that DVL plays a crucial role as a signaling hub in both Wnt/β-catenin as well as non-canonical Wnt pathways (4). Not only that, DVL has been reported to have multiple other functions -such as docking of basal body (5,6) and function and maintenance of primary cilia (7), cytokinesis (8) or positioning of the mitotic spindle (9), all possibly linked to the function of DVL in the regulation of centrosomal cycle (10).…”

Section: Introductionmentioning

confidence: 99%

Comparative phosphorylation map of Dishevelled3 (DVL3)

Hanáková

Bernatík

Ovesná

et al. 2019

Preprint

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One sentence summary:The study provides a comprehensive comparison of the phosphorylation of DVL3 induced by eight Ser/Thr kinases and identifies phosphorylation signatures associated with individual kinases. Abstract:In the presented study we analyze phosphorylation of human Dishevelled 3 (DVL3) induced by its previously reported (CK1ε, NEK2, PLK1, CK2α, RIPK4, PKCδ) and the newly identified (TTBK2, Aurora A) kinases. DVL3 contains 131 Ser/Thr whose phosphorylation generates complex barcodes underlying diverse DVL3 functions in Wnt pathways and other processes. We use quantitative mass spectrometry and via several complementary pipelines calculate site occupancies and quantify phosphorylation of >80 phosphorylated residues. In order to visualize the complex phosphorylation patterns, we design a novel visualization diagram, phosphoplot. Finally, we compare the individual sample and data processing approaches, identify their strengths and weaknesses. Subsequently, we verified a set of antiphospho-DVL antibodies and were able to successfully confirm induction for several of the phosphorylation sites. From the biological point of view, our data represent an important reference point and a toolbox for further analysis of DVL functions and phosphorylation events that control them. Acknowledgements:We would like to thank Erich Nigg (Biozentrum, Basel) for sharing reagents, Lumir Krejci for access to DV Elite and Lucie Smyčková, Lenka Bryjová and Naďa Bílá for excellent assistance.

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Section: Introductionmentioning

confidence: 99%

Comparative phosphorylation map of Dishevelled3 (DVL3)

Hanáková

Bernatík

Ovesná

et al. 2019

Preprint

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“…A crucial aspect of Wnt signaling is the ability of Dvl to interact with other proteins (Sharma et al, 2018). A Dvlinteracting protein that is involved in Wnt5a-mediated adhesion dynamics is Daple (Dvl-associating protein with a high frequency of leucine residues).…”

Section: Wnt5a In Gastric Cancer: Molecular Mechanismsmentioning

confidence: 99%

“…Nevertheless, lessons from studies about Disheveled and Wnt5a in GC might shed light on the mechanisms of Wnt signaling in other cancer types. On the other hand, considering the high number of Dvl-interacting proteins (reviewed in Sharma et al, 2018), there is still much to be learned from Dvl in GC.…”

Section: Wnt5a In Gastric Cancer: Molecular Mechanismsmentioning

confidence: 99%

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Wnt5a Signaling in Gastric Cancer

Astudillo

2020

Front. Cell Dev. Biol.

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Gastric cancer remains an important health challenge, accounting for a significant number of cancer-related deaths worldwide. Therefore, a deeper understanding of the molecular mechanisms involved in gastric cancer establishment and progression is highly desirable. The Wnt pathway plays a fundamental role in development, homeostasis, and disease, and abnormal Wnt signaling is commonly observed in several cancer types. Wnt5a, a ligand that activates the non-canonical branch of the Wnt pathway, can play a role as a tumor suppressor or by promoting cancer cell invasion and migration, although the molecular mechanisms explaining these roles have not been fully elucidated. Wnt5a is increased in gastric cancer samples; however, most gastric cancer cell lines seem to exhibit little expression of this ligand, thus raising the question about the source of this ligand in vivo. This review summarizes available research about Wnt5a expression and signaling in gastric cancer. In gastric cancer, Wnt5a promotes invasion and migration by modulating integrin adhesion turnover. Disheveled, a scaffolding protein with crucial roles in Wnt signaling, mediates the adhesion-related effects of Wnt5a in gastric cancer cells, and several studies provide growing support for a model whereby Disheveled-interacting proteins mediates Wnt5a signaling to modulate cytoskeleton dynamics. However, Wnt5a might induce other effects in gastric cancer cells, such as cell survival and induction of gene expression. On the other hand, the available evidence suggests that Wnt5a might be expressed by cells residing in the tumor microenvironment, where feedback mechanisms sustaining Wnt5a secretion and signaling might be established. This review analyzes the possible functions of Wnt5a in this pathological context and discusses potential links to mechanosensing and YAP/TAZ signaling.

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“…Researchers have long hypothesized there may be a secreted molecule (referred to as "Factor X" by (Lawrence et al, 2002)) that coordinates tissue-scale morphogenesis to the PCP pathway. Among the possible candidates for "Factor X", Wnt ligands have long been considered "obvious candidates for such factors" (Goodrich and Strutt, 2011) because both Fz and Dsh are highly conserved members of this signaling pathway: Fz and its paralog Fz2 function as co-receptors for Wnt ligands (Bhanot et al, 1999;Chen and Struhl, 1999;Müller et al, 1999), and Dsh is also a highly conserved component of the Wnt ligand-receptor signalosome (Perrimon and Mahowald, 1987;Sharma et al, 2018). However, a number of loss-of-function studies of Wnt ligands have failed to find any PCP phenotypes (Chen et al, 2008;Lawrence et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Wnt ligands are not required for planar cell polarity in theDrosophilawing or notum

Ewen-Campen

Comyn

Vogt

et al. 2020

Preprint

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The frizzled (fz) and disheveled (dsh) genes are highly conserved members of the core planar cell polarity (PCP) pathway and of the Wnt signaling pathway. Given these dual functions, a number of studies have examined whether Wnt ligands may provide a global, tissue-scale orientation cue for PCP establishment during development, and these studies have reached differing conclusions. In this study, we re-examine this issue in the Drosophila melanogaster wing and notum using split-Gal4 co-expression analysis, systematic pairwise and triple somatic CRISPR-based knock-outs and double RNAi experiments. Pairwise loss-of-function experiments targeting wg together with other Wnt genes does not produce PCP defects, neither via somatic CRISPR nor RNAi. In addition, somatic knock-out of evi (aka wntless), which is required for the secretion of all Wnt ligands expressed in these tissues, did not produce detectable PCP phenotypes. Altogether, we were unable to find support for the hypothesis that Wnt ligands contribute to PCP signaling in the Drosophila wing or notum.

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Dishevelled: A masterful conductor of complex Wnt signals

Cited by 166 publications

References 184 publications

Comparative phosphorylation map of Dishevelled3 (DVL3)

Comparative phosphorylation map of Dishevelled3 (DVL3)

Wnt5a Signaling in Gastric Cancer

Wnt ligands are not required for planar cell polarity in theDrosophilawing or notum

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