Density-Enhanced Protein Tyrosine Phosphatase 1 (DEP-1) Regulation of Epithelial Cell Adhesions

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  • March 22, 2019
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  • Sallee, Jennifer L.
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Cell-cell adhesions are critical to the development and maintenance of multicellular organisms. Increased tyrosine phosphorylation of junctional proteins has been associated with promoting disassembly of protein complexes at junctions and reducing cell-cell adhesions. Levels of tyrosine phosphorylation reflect the balance between protein-tyrosine kinase (PTK) and protein-tyrosine phosphatase (PTP) activity. DEP-1 is a receptor PTP which localizes to cell-cell adhesions and has been implicated in regulating phosphorylation of junctional proteins. The catalytically dead substrate-trapping mutant of DEP-1 (DEP-1 D/A) was used to identify additional substrates at cell-cell junctions. Members of the tight junction, occludin and ZO-1, were found to be substrates of DEP-1. DEP-1 D/A was not only able to bind these proteins in a tyrosine-phosphorylation dependent manner but wild type DEP-1 was able to dephosphorylate them. Occludin and ZO-1 interactions with DEP-1 were mediated through binding to the catalytic domain of DEP-1 and not by other protein-protein interaction motifs examined and appear to be specific to DEP-1. Over-expression of DEP-1 increased transepithelial electrical resistance in confluent epithelial monolayers and also reduced paracellular flux of FITC-dextran following a calcium switch. In addition, FAK and paxillin were also identified to be substrates of DEP-1 and indicate that DEP-1 could be regulating integrin adhesion-mediated signaling as well. Future work will focus on mapping the occludin residues necessary for DEP-1 interaction and will help to clarify potential signaling pathways and kinases upstream of DEP-1 activity. By controlling phosphotyrosine levels of tight junction proteins and perhaps focal adhesion proteins, DEP-1 may play a role in regulating permeability and junction formation in epithelial cells.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Cell and Developmental Biology.
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  • Burridge, Keith
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