Document Detail

Rac1 acts in conjunction with Nedd4 and dishevelled-1 to promote maturation of cell-cell contacts.
MedLine Citation:
PMID:  22467858     Owner:  NLM     Status:  MEDLINE    
The Rho-GTPase Rac1 promotes actin polymerization and membrane protrusion that mediate initial contact and subsequent maturation of cell-cell junctions. Here we report that Rac1 associates with the ubiquitin-protein ligase neural precursor cell expressed developmentally down-regulated 4 (Nedd4). This interaction requires the hypervariable C-terminal domain of Rac1 and the WW domains of Nedd4. Activated Rac1 colocalises with endogenous Nedd4 at epithelial cell-cell contacts. Reduction of Nedd4 expression by shRNA results in reduced transepithelial electrical resistance (TER) and concomitant changes in the distribution of adherens and tight junction markers. Conversely, expression of Nedd4 promotes TER, suggesting that Nedd4 cooperates with Rac1 in the induction of junctional maturation. We found that Nedd4, but not Nedd4-2, mediates the ubiquitylation and degradation of the adapter protein dishevelled-1 (Dvl1), the expression of which negatively regulates cell-cell contact. Nedd4-mediated ubiquitylation requires its binding to the C-terminal domain of Dvl1, comprising the DEP domain, and targets an N-terminal lysine-rich region upstream of the Dvl1 DIX domain. We found that endogenous Rac1 colocalises with endogenous Dvl1 in intracellular puncta as well as on cell-cell junctions. Finally, activated Rac1 was found to stimulate Nedd4 activity, resulting in increased ubiquitylation of Dvl1. Together, these data reveal a novel Rac1-dependent signalling pathway that, through Nedd4-mediated ubiquitylation of Dvl1, stimulates the maturation of epithelial cell-cell contacts.
Micha Nethe; Bart-Jan de Kreuk; Daniele V F Tauriello; Eloise C Anthony; Barbara Snoek; Thomas Stumpel; Patricia C Salinas; Madelon M Maurice; Dirk Geerts; André M Deelder; Paul J Hensbergen; Peter L Hordijk
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-30
Journal Detail:
Title:  Journal of cell science     Volume:  125     ISSN:  1477-9137     ISO Abbreviation:  J. Cell. Sci.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-09-07     Completed Date:  2013-03-25     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0052457     Medline TA:  J Cell Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  3430-42     Citation Subset:  IM    
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MeSH Terms
Adaptor Proteins, Signal Transducing / metabolism*
Adherens Junctions / metabolism
Amino Acid Sequence
Cell Adhesion / physiology*
Cell Communication / physiology*
Cell Line
Endosomal Sorting Complexes Required for Transport / metabolism*
HeLa Cells
Lung / cytology
Phosphoproteins / metabolism*
Protein Binding
Protein Structure, Tertiary
Signal Transduction
Ubiquitin-Protein Ligases / metabolism*
rac1 GTP-Binding Protein / metabolism*
Grant Support
G0802241//Medical Research Council
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Endosomal Sorting Complexes Required for Transport; 0/Phosphoproteins; 0/RAC1 protein, human; 0/dishevelled proteins; EC GTP-Binding Protein; EC ubiquitin protein ligases; EC Ligases

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