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Article: The Wnt coreceptor Ryk regulates Wnt/planar cell polarity by modulating the degradation of the core planar cell polarity component Vangl2

TitleThe Wnt coreceptor Ryk regulates Wnt/planar cell polarity by modulating the degradation of the core planar cell polarity component Vangl2
Authors
KeywordsAnimals
Body Patterning
Bone and Bones/embryology/metabolism
*Cell Polarity
Ear, Inner/embryology/metabolism
*Embryonic Development
HEK293 Cells
Hair Cells, Auditory, Inner/metabolism
Humans
Mice
Mice, Knockout
Nerve Tissue Proteins/chemistry/genetics/*metabolism
Neural Tube/embryology/metabolism
Protein Binding
Protein Stability
Proteolysis
Receptor Protein-Tyrosine Kinases/genetics/*metabolism
Signal Transduction
Wnt Proteins/genetics/*metabolism
Issue Date2012
Citation
Journal of Biological Chemistry, 2012, v. 287 n. 53, p. 44518-44525 How to Cite?
AbstractThe Wnt signaling pathways control many critical developmental and adult physiological processes. In vertebrates, one fundamentally important function of Wnts is to provide directional information by regulating the evolutionarily conserved planar cell polarity (PCP) pathway during embryonic morphogenesis. However, despite the critical roles of Wnts and PCP in vertebrate development and disease, little is known about the molecular mechanisms underlying Wnt regulation of PCP. Here, we have found that the receptor-like tyrosine kinase (Ryk), a Wnt5a-binding protein required in axon guidance, regulates PCP signaling. We show that Ryk interacts with Vangl2 genetically and biochemically, and such interaction is potentiated by Wnt5a. Loss of Ryk in a Vangl2(+/-) background results in classic PCP defects, including open neural tube, misalignment of sensory hair cells in the inner ear, and shortened long bones in the limbs. Complete loss of both Ryk and Vangl2 results in more severe phenotypes that resemble the Wnt5a(-/-) mutant in many aspects such as shortened anterior-posterior body axis, limb, and frontonasal process. Our data identify the Wnt5a-binding protein Ryk as a general regulator of the mammalian Wnt/PCP signaling pathway. We show that Ryk transduces Wnt5a signaling by forming a complex with Vangl2 and that Ryk regulates PCP by at least in part promoting Vangl2 stability. As human mutations in WNT5A and VANGL2 are found to cause Robinow syndrome and neural tube defects, respectively, our results further suggest that human mutations in RYK may also be involved in these diseases.
Persistent Identifierhttp://hdl.handle.net/10722/208444
ISSN
2015 SCImago Journal Rankings: 3.151
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorAndre, Pen_US
dc.contributor.authorWang, Qen_US
dc.contributor.authorWang, Nen_US
dc.contributor.authorGao, Ben_US
dc.contributor.authorSchilit, Aen_US
dc.contributor.authorHalford, MMen_US
dc.contributor.authorStacker, SAen_US
dc.contributor.authorZhang, Xen_US
dc.contributor.authorYang, Yen_US
dc.date.accessioned2015-03-11T03:01:03Z-
dc.date.available2015-03-11T03:01:03Z-
dc.date.issued2012en_US
dc.identifier.citationJournal of Biological Chemistry, 2012, v. 287 n. 53, p. 44518-44525en_US
dc.identifier.issn1083-351Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/208444-
dc.description.abstractThe Wnt signaling pathways control many critical developmental and adult physiological processes. In vertebrates, one fundamentally important function of Wnts is to provide directional information by regulating the evolutionarily conserved planar cell polarity (PCP) pathway during embryonic morphogenesis. However, despite the critical roles of Wnts and PCP in vertebrate development and disease, little is known about the molecular mechanisms underlying Wnt regulation of PCP. Here, we have found that the receptor-like tyrosine kinase (Ryk), a Wnt5a-binding protein required in axon guidance, regulates PCP signaling. We show that Ryk interacts with Vangl2 genetically and biochemically, and such interaction is potentiated by Wnt5a. Loss of Ryk in a Vangl2(+/-) background results in classic PCP defects, including open neural tube, misalignment of sensory hair cells in the inner ear, and shortened long bones in the limbs. Complete loss of both Ryk and Vangl2 results in more severe phenotypes that resemble the Wnt5a(-/-) mutant in many aspects such as shortened anterior-posterior body axis, limb, and frontonasal process. Our data identify the Wnt5a-binding protein Ryk as a general regulator of the mammalian Wnt/PCP signaling pathway. We show that Ryk transduces Wnt5a signaling by forming a complex with Vangl2 and that Ryk regulates PCP by at least in part promoting Vangl2 stability. As human mutations in WNT5A and VANGL2 are found to cause Robinow syndrome and neural tube defects, respectively, our results further suggest that human mutations in RYK may also be involved in these diseases.en_US
dc.languageengen_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.subjectAnimalsen_US
dc.subjectBody Patterningen_US
dc.subjectBone and Bones/embryology/metabolismen_US
dc.subject*Cell Polarityen_US
dc.subjectEar, Inner/embryology/metabolismen_US
dc.subject*Embryonic Developmenten_US
dc.subjectHEK293 Cellsen_US
dc.subjectHair Cells, Auditory, Inner/metabolismen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectMice, Knockouten_US
dc.subjectNerve Tissue Proteins/chemistry/genetics/*metabolismen_US
dc.subjectNeural Tube/embryology/metabolismen_US
dc.subjectProtein Bindingen_US
dc.subjectProtein Stabilityen_US
dc.subjectProteolysisen_US
dc.subjectReceptor Protein-Tyrosine Kinases/genetics/*metabolismen_US
dc.subjectSignal Transductionen_US
dc.subjectWnt Proteins/genetics/*metabolismen_US
dc.titleThe Wnt coreceptor Ryk regulates Wnt/planar cell polarity by modulating the degradation of the core planar cell polarity component Vangl2en_US
dc.typeArticleen_US
dc.identifier.emailGao, B: gaobo@hku.hken_US
dc.identifier.authorityGao, B=rp02012en_US
dc.identifier.doi10.1074/jbc.M112.414441en_US
dc.identifier.pmid23144463-
dc.identifier.pmcid3531765-
dc.identifier.scopuseid_2-s2.0-84871775384-
dc.identifier.volume287en_US
dc.identifier.issue53en_US
dc.identifier.spage44518en_US
dc.identifier.epage44525en_US
dc.identifier.isiWOS:000312938600048-

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