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PTK7 protein localization and stability is affected by canonical Wnt ligands

dc.contributor.advisorBorchers, Annette Prof. Dr.
dc.contributor.authorBerger, Hanna Irena
dc.date.accessioned2016-02-04T09:58:55Z
dc.date.available2016-02-04T09:58:55Z
dc.date.issued2016-02-04
dc.identifier.urihttp://hdl.handle.net/11858/00-1735-0000-0028-86B6-2
dc.identifier.urihttp://dx.doi.org/10.53846/goediss-5496
dc.language.isoengde
dc.relation.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc570de
dc.titlePTK7 protein localization and stability is affected by canonical Wnt ligandsde
dc.typedoctoralThesisde
dc.contributor.refereeBorchers, Annette Prof. Dr.
dc.date.examination2015-12-03
dc.description.abstractengWnt co-receptors have been shown to be endocytosed in response to Wnt proteins. However, the role of Wnt receptor internalization for Wnt signaling is a topic of ongoing research. Here we show that the Wnt co-receptor PTK7 (protein tyrosine kinase 7) is internalized via a caveolin-mediated pathway upon stimulation with canonical Wnt ligands. PTK7 is an evolutionary conserved transmembrane receptor that regulates a broad range of processes including the determination of planar cell polarity and the regulation of cell migration. Previous data from our lab revealed that PTK7 acts as Wnt co-receptor activating non-canonical PCP/Wnt signaling through Dsh-recruitment to the plasma membrane. Further, our findings indicate that PTK7 binds canonical but not non-canonical Wnt proteins and inhibits canonical Wnt signaling. This study shows that the cellular PTK7 protein localization is affected by canonical Wnt ligands. PTK7 is translocated from the plasma membrane to the cytoplasm upon Wnt3a stimulation. Interestingly, PTK7 and canonical Wnt proteins are internalized together as a ligand/receptor complex. In contrast, non-canonical Wnt ligands, which do not interact with PTK7, do not affect PTK7 membrane localization. PTK7 internalization is mediated by a caveolin-dependent pathway and prevented by inhibitors of caveolin-mediated endocytosis. Furthermore, we found evidence that canonical Wnt ligands trigger lysosomal PTK7 degradation. PTK7 protein levels decrease in response to canonical Wnt ligands, which does not happen after inhibition of lysosomal degradation. These data suggest a model of PTK7 function, whereby PTK7 likely inhibits canonical Wnt signaling by binding canonical Wnt ligands. Thereby canonical Wnt ligands are trapped in a PTK7-complex in the cytoplasm and their interaction with Wnt receptors supporting canonical Wnt signaling is prevented. Conversely, canonical Wnt proteins trigger PTK7 lysosomal degradation, indicating a mutual inhibition between canonical Wnt signaling and PTK7 signaling. In the context of caveolin-mediated internalization of PTK7, caveolin-1 depletion in Xenopus embryos was analyzed. Interestingly, caveolin-1 deficient embryos exhibit an impaired swimming behavior. Caveolin-1 is the best characterized member of the caveolin protein family, that includes three members in vertebrates, caveolin-1,-2 and -3. Here we show that caveolin-1 is strongly expressed in the notochord of Xenopus embryos and its depletion severely impairs swimming behavior. Co-injection of caveolin-1 mRNA rescues this swimming defect. Morphological studies in caveolin-1 morphant embryos revealed disrupted actin filaments in muscle cells of the somites. These findings indicate that defects in muscle development upon caveolin-1 depletion might result in the observed abnormal swimming behavior of Xenopus embryos.de
dc.contributor.coRefereeWodarz, Andreas Prof. Dr.
dc.subject.engPTK7de
dc.subject.engWnt signalingde
dc.subject.engEndocytosisde
dc.subject.engPCPde
dc.identifier.urnurn:nbn:de:gbv:7-11858/00-1735-0000-0028-86B6-2-8
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de
dc.identifier.ppn847151395


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