TY - JOUR
T1 - Dlg3 Trafficking and apical tight junction formation is regulated by Nedd4 and Nedd4-2 E3 Ubiquitin ligases
AU - Van Campenhout, Claude A.
AU - Eitelhuber, Andrea
AU - Gloeckner, Christian J.
AU - Giallonardo, Patrizia
AU - Gegg, Moritz
AU - Oller, Heide
AU - Grant, Seth G.N.
AU - Krappmann, Daniel
AU - Ueffing, Marius
AU - Lickert, Heiko
N1 - Funding Information:
We are thankful to Wenke Barkey for excellent technical assistance. We thank Tamara Caspary for the Arl13b antibody. We thank Anne Stephenson and Morgan Sheng for MAGUK expression vectors. We thank Perry Liao and Naomi Chadderton for valuable comments on the manuscript. This work was supported by the Helmholtz Society, a European Research Council Starting Grant and an Emmy-Noether fellowship from the German Research Foundation (DFG) awarded to H.L. This work was also supported by the EU grant SYSCILIA (HEALTH-F5-2010-241955; to M.U.) and the German Federal Ministry of Education and Research (BMBF: DYNAMO, FKZ: 0315513A; to M.U.) C.A.V.C. was the recipient of an Alexander von Humboldt Foundation scholarship.
PY - 2011/9/13
Y1 - 2011/9/13
N2 - The Drosophila Discs large (Dlg) scaffolding protein acts as a tumor suppressor regulating basolateral epithelial polarity and proliferation. In mammals, four Dlg homologs have been identified; however, their functions in cell polarity remain poorly understood. Here, we demonstrate that the X-linked mental retardation gene product Dlg3 contributes to apical-basal polarity and epithelial junction formation in mouse organizer tissues, as well as to planar cell polarity in the inner ear. We purified complexes associated with Dlg3 in polarized epithelial cells, including proteins regulating directed trafficking and tight junction formation. Remarkably, of the four Dlg family members, Dlg3 exerts a distinct function by recruiting the ubiquitin ligases Nedd4 and Nedd4-2 through its PPxY motifs. We found that these interactions are required for Dlg3 monoubiquitination, apical membrane recruitment, and tight junction consolidation. Our findings reveal an unexpected evolutionary diversification of the vertebrate Dlg family in basolateral epithelium formation.
AB - The Drosophila Discs large (Dlg) scaffolding protein acts as a tumor suppressor regulating basolateral epithelial polarity and proliferation. In mammals, four Dlg homologs have been identified; however, their functions in cell polarity remain poorly understood. Here, we demonstrate that the X-linked mental retardation gene product Dlg3 contributes to apical-basal polarity and epithelial junction formation in mouse organizer tissues, as well as to planar cell polarity in the inner ear. We purified complexes associated with Dlg3 in polarized epithelial cells, including proteins regulating directed trafficking and tight junction formation. Remarkably, of the four Dlg family members, Dlg3 exerts a distinct function by recruiting the ubiquitin ligases Nedd4 and Nedd4-2 through its PPxY motifs. We found that these interactions are required for Dlg3 monoubiquitination, apical membrane recruitment, and tight junction consolidation. Our findings reveal an unexpected evolutionary diversification of the vertebrate Dlg family in basolateral epithelium formation.
UR - http://www.scopus.com/inward/record.url?scp=80052776738&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2011.08.003
DO - 10.1016/j.devcel.2011.08.003
M3 - Article
C2 - 21920314
AN - SCOPUS:80052776738
SN - 1534-5807
VL - 21
SP - 479
EP - 491
JO - Developmental Cell
JF - Developmental Cell
IS - 3
ER -