title: PTK7 modulates Wnt signaling activity via LRP6.
abstract: Protein tyrosine kinase 7 (PTK7) is a transmembrane protein expressed in the developing Xenopus neural plate. PTK7 regulates vertebrate planar cell polarity (PCP), controlling mesodermal and neural convergent-extension (CE) cell movements, neural crest migration and neural tube closure in vertebrate embryos. Besides CE phenotypes, we now show that PTK7 protein knockdown also inhibits Wnt/β-catenin activity. Canonical Wnt signaling caudalizes the neural plate via direct transcriptional activation of the meis3 TALE-class homeobox gene, which subsequently induces neural CE. PTK7 controls meis3 gene expression to specify posterior tissue and downstream PCP activity. Furthermore, PTK7 morphants phenocopy embryos depleted for Wnt3a, LRP6 and Meis3 proteins. PTK7 protein depletion inhibits embryonic Wnt/β-catenin signaling by strongly reducing LRP6 protein levels. LRP6 protein positively modulates Wnt/β-catenin, but negatively modulates Wnt/PCP activities. The maintenance of high LRP6 protein levels by PTK7 triggers PCP inhibition. PTK7 and LRP6 proteins physically interact, suggesting that PTK7 stabilization of LRP6 protein reciprocally regulates both canonical and noncanonical Wnt activities in the embryo. We suggest a novel role for PTK7 protein as a modulator of LRP6 that negatively regulates Wnt/PCP activity.
authors.affiliation: Department of Biochemistry, The Rappaport Family Institute for Research in the Medical Sciences, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Naama
authors.initials: N
authors.lastname: Bin-Nun
authors.forename: Hava
authors.initials: H
authors.lastname: Lichtig
authors.forename: Anastasia
authors.initials: A
authors.lastname: Malyarova
authors.forename: Michal
authors.initials: M
authors.lastname: Levy
authors.forename: Sara
authors.initials: S
authors.lastname: Elias
authors.forename: Dale
authors.initials: D
authors.lastname: Frank
mesh_terms: D000818:Animals; D016764:Cell Polarity; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054258:Neural Plate / Q000196:embryology / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D029867:Xenopus Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C491174:Meis3 protein, Xenopus; D011994:Recombinant Proteins; D029867:Xenopus Proteins; C487768:PTK7 protein, Xenopus; D020794:Receptor Protein-Tyrosine Kinases
keywords: LRP6 protein; Neural patterning; Planar cell polarity; Protein tyrosine kinase 7 (PTK7); Wnt/β-catenin; Xenopus