Dishevelled (Dvl-2) activates canonical Wnt signalling in the absence of cytoplasmic puncta

Smalley, Matthew J.; Signoret, Nathalie; Robertson, David; Tilley, Alan; Hann, A. C.; Ewan, Kenneth; Ding, Yichuan; Paterson, Hugh; Dale, Trevor

doi:10.1242/jcs.02647

Cited by 71 publications

(80 citation statements)

References 55 publications

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“…S3). Phosphorylation at S643 was associated with homogenous cytoplasmic localization of DVL3 (27), and indeed NEK2, similar to casein kinase (CK)1e coexpression (28,29), triggered subcellular relocalization of DVL from punctate to even cytoplasmic distribution (SI Appendix, Fig. S2D).…”

Section: Resultsmentioning

confidence: 95%

Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins

Červenka

Valnohová

Bernatík

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Dishevelled (DVL) is a key scaffolding protein and a branching point in Wnt signaling pathways. Here, we present conclusive evidence that DVL regulates the centrosomal cycle. We demonstrate that DVL dishevelled and axin (DIX) domain, but not DIX domain-mediated multimerization, is essential for DVL's centrosomal localization. DVL accumulates during the cell cycle and associates with NIMA-related kinase 2 (NEK2), which is able to phosphorylate DVL at a multitude of residues, as detected by a set of novel phospho-specific antibodies. This creates interfaces for efficient binding to CDK5 regulatory subunitassociated protein 2 (CDK5RAP2) and centrosomal Nek2-associated protein 1 (C-NAP1), two proteins of the centrosomal linker. Displacement of DVL from the centrosome and its release into the cytoplasm on NEK2 phosphorylation is coupled to the removal of linker proteins, an event necessary for centrosomal separation and proper formation of the mitotic spindle. Lack of DVL prevents NEK2-controlled dissolution of loose centrosomal linker and subsequent centrosomal separation. Increased DVL levels, in contrast, sequester centrosomal NEK2 and mimic monopolar spindle defects induced by a dominant negative version of this kinase. Our study thus uncovers molecular crosstalk between centrosome and Wnt signaling.Wnt signaling | centrosome | Dishevelled | NEK2 | linker proteins

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Section: Resultsmentioning

confidence: 95%

Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins

Červenka

Valnohová

Bernatík

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…However, these studies do not address whether Dvl-1 is ubiquitylated prior to the interaction with NKD2. Additional studies are necessary to determine the stoichiometry of the NKD2-Dvl-1 interaction and the complete composition of this complex, including the E3 ligase(s) that execute their degradation (37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Myristoylated Naked2 Antagonizes Wnt-β-Catenin Activity by Degrading Dishevelled-1 at the Plasma Membrane

Cao

et al. 2010

Journal of Biological Chemistry

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In Drosophila, naked cuticle is an inducible antagonist of the Wnt-␤-catenin pathway, likely acting at the level of Dishevelled (Dsh/Dvl), an essential component of this pathway. The mechanism by which naked cuticle and its two vertebrate orthologs, Naked1 (NKD1) and Naked2 (NKD2), inhibit Dvl function is unknown. NKD2 is myristoylated, a co-translational modification that leads to its plasma membrane localization. In contrast, myristoylation-deficient G2A NKD2 is cytoplasmic. Herein we show that the ability of Nkd2/NKD2 to antagonize Wnt-␤-catenin activity during zebrafish embryonic development and in mammalian HEK293 cells is myristoylation-dependent. NKD2 and Dvl-1 interact and co-localize at the lateral membrane of polarized epithelial cells. In reciprocal overexpression and siRNA knockdown experiments, NKD2 and Dvl-1 destabilize each other via enhanced polyubiquitylation; this effect is also dependent upon Naked2 myristoylation. Cell fractionation and ubiquitylation assays indicate that endogenous NKD2 interacts with a slower migrating, ubiquitylated form of Dvl-1 in plasma membrane fractions. These results provide a mechanism by which NKD2 antagonizes Wnt signaling: myristoylated NKD2 interacts with Dvl-1 at the plasma membrane, and this interaction leads to their mutual ubiquitin-mediated proteasomal degradation.

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“…We fused a Dishevelled truncation known to specifically activate the non-canonical Wnt pathway (Rothbacher et al, 2000;Wallingford and Habas, 2005) to the ligand binding domain of the human glucocorticoid receptor (GR). The obtained fusion construct called dshDDIXGR was first tested and found to specifically activate non-canonical Wnt signaling (Afouda and Hoppler, unpublished data; see also Smalley et al, 2005). Interestingly, reduction of cardiogenic marker expression caused by inhibition of GATA4 and GATA6 is rescued when the non-canonical pathway is activated, both in animal cap and dorsal marginal zone explants (Fig.…”

Section: Non-canonical Wnt Signaling Mediates the Differential Requirmentioning

confidence: 95%

“…The dshDDIXGR is a hormone-inducible construct of the Dishevelled protein without the DIX (nucleotides 1 to 480) domain (Afouda and Hoppler, in press;Smalley et al, 2005). All injected RNAs were synthesized using mMESSAGE mMACHINE kits (Ambion, Austin, TX).…”

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confidence: 99%

Different requirements for GATA factors in cardiogenesis are mediated by non‐canonical Wnt signaling

Afouda¹,

Hoppler²

2011

Developmental Dynamics

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GATA factors and Wnt signals are key regulators of vertebrate cardiogenesis, but specific roles for individual GATA factors and how they interact with Wnt signaling remain unknown. We use loss of function and overexpression approaches to elucidate how these molecules regulate early cardiogenesis in Xenopus. In order to minimize indirect effects due to abnormal early embryogenesis, we use pluripotent embryonic tissues as cardiogenic assays. We confirm central roles for GATA4, 5, and 6 in cardiogenesis, but also discover individual and different requirements. We show that GATA4 or 6 regulate both cardiogenic potential and subsequent cardiomyocyte differentiation but that GATA5 is involved in regulating cardiomyocyte differentiation. We also show that Wnt11b signaling can rescue reduced cardiac differentiation resulting from loss of function of GATA4 and 6 but not GATA5. We conclude that Wnt11b mediates the differential requirements for GATA factors during vertebrate cardiogenesis. Developmental Dynamics 240:649-662,

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Dishevelled (Dvl-2) activates canonical Wnt signalling in the absence of cytoplasmic puncta

Cited by 71 publications

References 55 publications

Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins

Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins

Myristoylated Naked2 Antagonizes Wnt-β-Catenin Activity by Degrading Dishevelled-1 at the Plasma Membrane

Different requirements for GATA factors in cardiogenesis are mediated by non‐canonical Wnt signaling

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