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Identifying downstream mediators linking JAM‐A to Barrier Function
Author(s) -
Monteiro Ana Carolina,
Rankin Carl Robert,
Severson Eric A,
Nusrat Asma,
Parkos Charles A
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.242.5
Subject(s) - pdz domain , microbiology and biotechnology , tight junction , chemistry , barrier function , scaffold protein , nectin , claudin , gtpase , transmembrane protein , small gtpase , cell adhesion , biology , signal transduction , cell , biochemistry , receptor
Intestinal barrier function is regulated by epithelial tight junctions (TJs), allowing for absorption of nutrients and exclusion of unwanted substances. A TJ‐associated transmembrane protein shown to play a role in regulation of barrier function is Junctional Adhesion Molecule‐A (JAM‐A). JAM‐A has a short cytoplasmic tail that associates with scaffold proteins and two extracellular immunoglobulin‐like domains that allow for its homodimerization on the surface of the same cell. Despite several structural and functional studies, mechanistic details linking JAM‐A to TJ regulation is lacking. We have previously shown that JAM‐A dimerization affects epithelial cell migration through close apposition of PDZ‐GEF2 and Afadin resulting in activation of the small GTPase Rap1a. We now report that knockdown of Afadin and PDZ‐GEF1 and 2, but not Rap1a or Rap1b, impair barrier function in vitro. Given that loss of Rap1 did not affect barrier, we assessed the role of other GTPases activated by PDZ‐GEFs and determined that knockdown of Rap2 disrupts barrier in a manner similar to that observed with loss of JAM‐A. In addition, our preliminary studies suggest that JAM‐A dimerization differentially regulates expression of barrier‐forming claudin proteins. These findings suggest that JAM‐A clusters Afadin and PDZ‐GEFs to activate Rap2 and regulate barrier by altering the protein composition of TJs(Supported by NIH DK061379)