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Pervanadate‐induced shedding of the intercellular adhesion molecule (ICAM)‐1 ectodomain is mediated by membrane type‐1 matrix metalloproteinase (MT1‐MMP)
Author(s) -
Essick Eric E.,
Sithu Srinivas D.,
Dean William,
D'souza Stanley E.
Publication year - 2008
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.22.1_supplement.964.10
Subject(s) - ectodomain , microbiology and biotechnology , chemistry , matrix metalloproteinase , metalloproteinase , icam 1 , disintegrin , intercellular adhesion molecule 1 , cell adhesion molecule , adam10 , intracellular , biochemistry , biology , receptor
Intercellular adhesion molecule(ICAM)‐1 is a member of the immunoglobin(Ig)‐like family of endothelial cell (EC) adhesion molecules responsible for adhesive interactions with circulating leukocytes, necessary for subsequent transmigration to damaged tissues. In several vascular diseases, the ectodomain of ICAM‐1 becomes cleaved by a zinc‐dependent endopeptidase, releasing a soluble form of the protein (sICAM‐1), a common marker for inflammatory diseases. Since several reactive oxygen species (ROS) generated during conditions of oxidative stress are known to induce endopeptidase‐mediated cleavage of transmembrane proteins, we sought to explore the cleavage and enzymatic effects that the ROS pervanadate, a protein tyrosine phosphatase inhibitor, has on ICAM‐1 cleavage. Our data indicates that pervanadate treatment of ECs and human embryonic kidney (HEK) 293 cells expressing ICAM‐1 results in shedding of its ectodomain. Furthermore, by employing specific tissue inhibitors of metalloproteinases (TIMPs) and small interfering(si) RNA against endopeptidase activity, we found that this cleavage is mediated by membrane type‐1 matrix metalloproteinase (MT1‐MMP). Confocal microscopy provides evidence that ICAM‐1 and MT1‐MMP colocalize at the cellular surface following pervanadate treatment, further implicating the involvement of MT1‐MMP in this mode of ICAM‐1 shedding.