title: The Myopic-Ubpy-Hrs nexus enables endosomal recycling of Frizzled.
abstract: Endosomal trafficking of signaling proteins plays an essential role in cellular homeostasis. The seven-pass transmembrane protein Frizzled (Fz) is a critical component of Wnt signaling. Although Wnt signaling is proposed to be regulated by endosomal trafficking of Fz, the molecular events that enable this regulation are not completely understood. Here we show that the endosomal protein Myopic (Mop) regulates Fz trafficking in the Drosophila wing disk by inhibiting the ubiquitination and degradation of Hrs. Deletion of Mop or Hrs results in endosomal accumulation of Fz and therefore reduced Wnt signaling. The in situ proximity ligation assay revealed a strong association between Mop and Hrs in the Drosophila wing disk. Overexpression of Hrs rescues the trafficking defect caused by mop knockdown. Mop aids in the maintenance of Ubpy, which deubiquitinates (and thus stabilizes) Hrs. In the absence of the ubiquitin ligase Cbl, Mop is dispensable. These findings support a previously unknown role for Mop in endosomal trafficking of Fz in Wnt-receiving cells.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
authors.forename: Tirthadipa
authors.initials: T
authors.lastname: Pradhan-Sundd
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada everheye@sfu.ca.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Verheyen
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D004705:Endocytosis; D010450:Endopeptidases / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D051157:Frizzled Receptors / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D021381:Protein Transport; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D051157:Frizzled Receptors; D010750:Phosphoproteins; D025801:Ubiquitin; C058784:fz protein, Drosophila; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C549822:Mop protein, Drosophila; D017027:Protein Tyrosine Phosphatases; D010450:Endopeptidases; C059237:ubiquitin-Nalpha-protein hydrolase