title: Gliotactin and Discs large are co-regulated to maintain epithelial integrity.
abstract: Establishment and maintenance of permeability barriers is one of the most important functions of epithelial cells. Tricellular junctions (TCJs) maintain the permeability barriers at the contact site of three epithelial cells. Gliotactin, a member of the Neuroligin family, is the only known Drosophila protein exclusively localized to the TCJ and is necessary for maintenance of the permeability barrier. Overexpression triggers the spread of Gliotactin away from the TCJ and causes epithelial cells to delaminate, migrate and die. Furthermore, excess Gliotactin at the cell membrane results in an extensive downregulation of Discs large (Dlg) at the septate junctions. The intracellular domain of Gliotactin contains two highly conserved tyrosine residues and a PDZ binding motif. We previously found that phosphorylation of the tyrosine residues is necessary to control the level of Gliotactin at the TCJ. In this study we demonstrate that the phenotypes associated with excess Gliotactin are due to a functional interaction between Gliotactin and Dlg that is dependent on both tyrosine phosphorylation as well as the PDZ binding motif. We further show that elevated levels of Dlg strongly enhance Gliotactin overexpression phenotypes to the point where tissue over-growth is observed. The exhibition of these phenotypes require phosphorylation of Dlg on serine 797, a known Par1 phosphorylation target. Blocking this phosphorylation completely suppresses the cell invasiveness and apoptotic phenotypes associated with Gliotactin overexpression. Additionally, we show that Drosophila JNK acts downstream of Gliotactin and Dlg to mediate the overgrowth and apoptosis caused by the functional interaction of Gliotactin and Dlg.
authors: Department of Zoology, Cell and Developmental Biology, University of British Columbia, Vancouver V6T 1Z3, Canada.
authors: Mojgan
authors: M
authors: Padash-Barmchi
authors: Kristi
authors: K
authors: Charish
authors: Jammie
authors: J
authors: Que
authors: Vanessa J
authors: VJ
authors: Auld
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D007365:Intercellular Junctions / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; C094064:gliotactin; C070350:dlg1 protein, Drosophila