Scribble Regulates Cell Adhesion

Lohia, Madhura, Department of Microbiology, University of Virginia
Macara, Ian, Department of Microbiology, University of Virginia
Parsons, Tom, Department of Microbiology, University of Virginia
Adler, Paul, Department of Biology, University of Virginia
Sutherland, Ann, Department of Cell Biology, University of Virginia
Ravichandran, Kodi, Department of Microbiology, University of Virginia

Cell-cell adhesion is an essential process for proper formation and maintenance of tissues. In epithelial tissue, neighboring cells form contacts through a variety of protein complexes that are evolutionarily conserved. E- cadherin is a core member of one such complex, present at adherens junctions. It is a transmembrane protein, which functions by binding to partner E-cadherin molecules present on the extracellular surface of adjacent cells, and to other conserved proteins on the intracellular side of the membrane thereby forming links to the underlying cytoskeleton. Previously, our laboratory has shown that suppressing the expression of the polarity protein Scribble (Scrb) leads to a reduction in E-cadherin mediated cell-cell adhesion in MDCK epithelial cells, but how this occurs was unclear. We now find that depletion of Scrb weakens the E-cadherin-p120catenin interaction, resulting in decreased junctional stability of the cadherin-catenin complex and the presence of E-cadherin in intracellular vesicles. p120catenin associates with Scrb and this association requires the first two PDZ domains of Scrb, which are necessary for cell adhesion. Additionally we find that the adherens junctionassociated protein -actinin no longer binds E-cadherin and is lost from junctions upon Scrb depletion. Silencing -actinin also causes a loss of cell-cell adhesion, and actin re-organization, but does not affect the binding of E-cadherin to ii p120catenin. We propose that Scrb promotes the coupling of E-cadherin to p120catenin and -actinin, thus stabilizing the cadherin complex at junctions to enhance cell-cell adhesion. In mammalian systems, Scribble functions as a regulator of planar cell polarity. Planar cell polarity defects are seen in a number of mouse mutants including those for the tetraspanin protein Vangl2, the transmembrane protein PTK7, the mammalian homolog of Dishevelled as well as mice expressing a mutant form of Scribble. We find that in MDCK epithelial cells this group of proteins is involved in the regulation of cell-cell adhesion. We propose that planar cell polarity proteins modulate inter-cell adhesion to affect the polarity of cell within the plane of an epithelium.

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PHD (Doctor of Philosophy)
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