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1 Physiology, University of Louisville, Louisville, KY, USA
2 Oncology, Institute of Medical Research, Cambridge, United Kingdom
* To whom correspondence should be addressed. E-mail: sedsou01{at}gwise.louisville.edu.
ICAM-1, a membrane-bound receptor, is released as soluble ICAM-1 in inflammatory diseases. To delineate mechanisms regulating ICAM-1 cleavage, studies were performed in endothelial cells (EC) and in 293 cells transfected with wild type ICAM-1 (WT), and ICAM-1 containing single tyrosine (Y) to alanine (A) substitutions in the cytoplasmic region - Y474A, Y476A and Y485A. Tyrosine residues at 474 and 485 become phosphorylated upon ICAM-1 ligation and associate with signaling modules. Cleavage was assessed using an antibody against cytoplasmic tail of ICAM-1, which recognizes intact ICAM-1 and the 7 kDa membrane-bound fragment remaining after cleavage. Cleavage in 293 WT was accelerated by phorbol ester PMA, whilst in EC it was induced by TNF
. In both cell types a 7 kDa ICAM-1 remnant was detected. Tyrosine phosphatase inhibitors dephostatin and sodium orthovanadate augmented cleavage. PD98059 (MEK inhibitor), geldanamycin and PP2 (Src kinase inhibitors) and wortmannin (PI3-kinase inhibitor) dose-dependently inhibited cleavage in both cell types. SB203580 (p38 inhibitor) was more effective in EC, while D609 (phospholipase C inhibitor) mostly affected cleavage in 293 cells. Cleavage however was drastically decreased in Y474A and Y485A, while in Y476A it was marginally reduced. Surprisingly, phosphorylation was not detectable on 7 kDa fragment of ICAM-1. These results implicate distinct pathways in the cleavage process and suggest preferred signal transmission route for ICAM-1 shedding in the two cell systems tested. Tyrosine residues Y474 and Y485 within cytoplasmic sequence of ICAM-1 regulate the cleavage process.
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