Control of Gliotactin localization and levels by tyrosine phosphorylation and endocytosis is necessary for survival of polarized epithelia.
The tricellular junction (TCJ) forms at the convergence of bicellular junctions from three adjacent cells in polarized epithelia and is necessary for maintaining the transepithelial barrier. In the fruitfly Drosophila, the TCJ is generated at the meeting point of bicellular septate junctions. Gliotactin was the first identified component of the TCJ and is necessary for TCJ and septate junction development. Gliotactin is a member of the neuroligin family and associates with the PDZ protein discs large. Beyond this interaction, little is known about the mechanisms underlying Gliotactin localization and function at the TCJ. In this study, we show that Gliotactin is phosphorylated at conserved tyrosine residues, a process necessary for endocytosis and targeting to late endosomes and lysosomes for degradation. Regulation of Gliotactin levels through phosphorylation and endocytosis is necessary as overexpression results in displacement of Gliotactin away from the TCJ throughout the septate junction domain. Excessive Gliotactin in polarized epithelia leads to delamination, paired with subsequent migration, and apoptosis. The apoptosis and the resulting compensatory proliferation resulting from high levels of Gliotactin are mediated by the Drosophila JNK pathway. Therefore, Gliotactin levels within the cell membrane are regulated to ensure correct protein localization and cell survival.
Department of Zoology, Cell and Developmental Biology, University of British Columbia, Vancouver, Canada BC V6T 1Z3.
Mojgan
M
Padash-Barmchi
Kristen
K
Browne
Kendra
K
Sturgeon
Barbara
B
Jusiak
Vanessa J
VJ
Auld
D020816:Amino Acid Motifs; D000818:Animals; D016764:Cell Polarity; D049109:Cell Proliferation; D002470:Cell Survival; D004330:Drosophila / Q000737:chemistry / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D007365:Intercellular Junctions / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C094064:gliotactin