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Autoinhibition of Dishevelled protein regulated by its extreme C terminus plays a distinct role in Wnt/β-catenin and Wnt/planar cell polarity (PCP) signaling pathways.
Qi J
,
Lee HJ
,
Saquet A
,
Cheng XN
,
Shao M
,
Zheng JJ
,
Shi DL
.
???displayArticle.abstract??? Dishevelled (Dvl) is a key intracellular signaling molecule that mediates the activation of divergent Wnt pathways. It contains three highly conserved domains known as DIX, PDZ, and DEP, the functions of which have been well characterized in β-catenin-dependent canonical and β-catenin-independent noncanonical Wnt signaling. The C-terminal region is also highly conserved from invertebrates to vertebrates. However, its function in regulating the activation of different Wnt signals remains unclear. We reported previously that Dvl conformational change triggered by the highly conserved PDZ-binding C terminus is important for the pathway specificity. Here we provide further evidence demonstrating that binding of the C terminus to the PDZ domain results in Dvl autoinhibition in the Wnt signaling pathways. Therefore, the forced binding of the C terminus to the PDZ domain reduces the activity of Dvl in noncanonical Wnt signaling, whereas obstruction of this interaction releases Dvl autoinhibition, impairs its functional interaction with LRP6 in canonical Wnt signaling, and increases its specificity in noncanonical Wnt signaling, which is closely correlated with an enhanced Dvl membrane localization. Our findings highlight the importance of the C terminus in keeping Dvl in an appropriate autoinhibited state, accessible for regulation by other partners to switch pathway specificity. Particularly, the C-terminally tagged Dvl fusion proteins that have been widely used to study the function and cellular localization of Dvl may not truly represent the wild-type Dvl because those proteins cannot be autoinhibited.
Anastas,
WNT signalling pathways as therapeutic targets in cancer.
2013, Pubmed
Anastas,
WNT signalling pathways as therapeutic targets in cancer.
2013,
Pubmed
Angers,
The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation.
2006,
Pubmed
,
Xenbase
Angers,
Proximal events in Wnt signal transduction.
2009,
Pubmed
Axelrod,
Unipolar membrane association of Dishevelled mediates Frizzled planar cell polarity signaling.
2001,
Pubmed
Axelrod,
Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways.
1998,
Pubmed
,
Xenbase
Bilic,
Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation.
2007,
Pubmed
Boutros,
Dishevelled: at the crossroads of divergent intracellular signaling pathways.
1999,
Pubmed
,
Xenbase
Boutros,
Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling.
1998,
Pubmed
Cao,
The PDZ-containing unconventional myosin XVIIIA regulates embryonic muscle integrity in zebrafish.
2014,
Pubmed
Cao,
High mobility group B proteins regulate mesoderm formation and dorsoventral patterning during zebrafish and Xenopus early development.
2012,
Pubmed
,
Xenbase
Capelluto,
The DIX domain targets dishevelled to actin stress fibres and vesicular membranes.
2002,
Pubmed
,
Xenbase
Carreira-Barbosa,
Flamingo regulates epiboly and convergence/extension movements through cell cohesive and signalling functions during zebrafish gastrulation.
2009,
Pubmed
Clevers,
Wnt/β-catenin signaling and disease.
2012,
Pubmed
Djiane,
Role of frizzled 7 in the regulation of convergent extension movements during gastrulation in Xenopus laevis.
2000,
Pubmed
,
Xenbase
Gammons,
Wnt Signalosome Assembly by DEP Domain Swapping of Dishevelled.
2016,
Pubmed
Gammons,
Essential role of the Dishevelled DEP domain in a Wnt-dependent human-cell-based complementation assay.
2016,
Pubmed
Gao,
Dishevelled: The hub of Wnt signaling.
2010,
Pubmed
Goodrich,
Principles of planar polarity in animal development.
2011,
Pubmed
Habas,
Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1.
2001,
Pubmed
,
Xenbase
He,
A WNTer wonderland in Snowbird.
2006,
Pubmed
Kim,
Ryk cooperates with Frizzled 7 to promote Wnt11-mediated endocytosis and is essential for Xenopus laevis convergent extension movements.
2008,
Pubmed
,
Xenbase
Kimmel,
Stages of embryonic development of the zebrafish.
1995,
Pubmed
,
Xenbase
Lee,
Identification of transmembrane protein 88 (TMEM88) as a dishevelled-binding protein.
2010,
Pubmed
,
Xenbase
Lee,
Conformational change of Dishevelled plays a key regulatory role in the Wnt signaling pathways.
2015,
Pubmed
,
Xenbase
Lee,
PDZ domains and their binding partners: structure, specificity, and modification.
2010,
Pubmed
Li,
The RNA-binding protein Seb4/RBM24 is a direct target of MyoD and is required for myogenesis during Xenopus early development.
2010,
Pubmed
,
Xenbase
Li,
The Xenopus homologue of Down syndrome critical region protein 6 drives dorsoanterior gene expression and embryonic axis formation by antagonising polycomb group proteins.
2013,
Pubmed
,
Xenbase
Li,
Dishevelled proteins lead to two signaling pathways. Regulation of LEF-1 and c-Jun N-terminal kinase in mammalian cells.
1999,
Pubmed
Liu,
Mechanism of activation of the Formin protein Daam1.
2008,
Pubmed
,
Xenbase
Logan,
The Wnt signaling pathway in development and disease.
2004,
Pubmed
Ma,
Dishevelled-3 C-terminal His single amino acid repeats are obligate for Wnt5a activation of non-canonical signaling.
2010,
Pubmed
MacDonald,
Wnt/beta-catenin signaling: components, mechanisms, and diseases.
2009,
Pubmed
,
Xenbase
MacDonald,
Wnt signal amplification via activity, cooperativity, and regulation of multiple intracellular PPPSP motifs in the Wnt co-receptor LRP6.
2008,
Pubmed
,
Xenbase
Miller,
Establishment of the dorsal-ventral axis in Xenopus embryos coincides with the dorsal enrichment of dishevelled that is dependent on cortical rotation.
1999,
Pubmed
,
Xenbase
Mlodzik,
The Dishevelled Protein Family: Still Rather a Mystery After Over 20 Years of Molecular Studies.
2016,
Pubmed
Moriguchi,
Distinct domains of mouse dishevelled are responsible for the c-Jun N-terminal kinase/stress-activated protein kinase activation and the axis formation in vertebrates.
1999,
Pubmed
,
Xenbase
Niehrs,
The complex world of WNT receptor signalling.
2012,
Pubmed
Ohkawara,
Rspo3 binds syndecan 4 and induces Wnt/PCP signaling via clathrin-mediated endocytosis to promote morphogenesis.
2011,
Pubmed
,
Xenbase
Park,
Subcellular localization and signaling properties of dishevelled in developing vertebrate embryos.
2005,
Pubmed
,
Xenbase
Rothbächer,
Dishevelled phosphorylation, subcellular localization and multimerization regulate its role in early embryogenesis.
2000,
Pubmed
,
Xenbase
Shao,
Down syndrome critical region protein 5 regulates membrane localization of Wnt receptors, Dishevelled stability and convergent extension in vertebrate embryos.
2009,
Pubmed
,
Xenbase
Simons,
Electrochemical cues regulate assembly of the Frizzled/Dishevelled complex at the plasma membrane during planar epithelial polarization.
2009,
Pubmed
Singh,
Planar cell polarity signaling: coordination of cellular orientation across tissues.
2012,
Pubmed
Singh,
Abelson family kinases regulate Frizzled planar cell polarity signaling via Dsh phosphorylation.
2010,
Pubmed
Sokol,
Analysis of Dishevelled signalling pathways during Xenopus development.
1996,
Pubmed
,
Xenbase
Tamai,
A mechanism for Wnt coreceptor activation.
2004,
Pubmed
,
Xenbase
Tauriello,
Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled.
2012,
Pubmed
,
Xenbase
Tree,
Prickle mediates feedback amplification to generate asymmetric planar cell polarity signaling.
2002,
Pubmed
Umbhauer,
The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/beta-catenin signalling.
2000,
Pubmed
,
Xenbase
Wallingford,
Dishevelled controls cell polarity during Xenopus gastrulation.
2000,
Pubmed
,
Xenbase
Wallingford,
The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity.
2005,
Pubmed
Wang,
Tissue/planar cell polarity in vertebrates: new insights and new questions.
2007,
Pubmed
Wang,
Dishevelled C-terminus: prolyl and histidinyl motifs.
2012,
Pubmed
Wang,
Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation.
2006,
Pubmed
,
Xenbase
Weitzel,
Differential stability of beta-catenin along the animal-vegetal axis of the sea urchin embryo mediated by dishevelled.
2004,
Pubmed
Wong,
Structural basis of the recognition of the dishevelled DEP domain in the Wnt signaling pathway.
2000,
Pubmed
Wong,
Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled.
2003,
Pubmed
,
Xenbase
Yanfeng,
Functional dissection of phosphorylation of Disheveled in Drosophila.
2011,
Pubmed
Yang,
Wnt-Frizzled/planar cell polarity signaling: cellular orientation by facing the wind (Wnt).
2015,
Pubmed
Zeng,
A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation.
2005,
Pubmed
,
Xenbase
Zeng,
Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions.
2008,
Pubmed
,
Xenbase
