Molecular events associated with CD4-mediated down-regulation of LFA-1-dependent adhesion

被引:11
作者
Mazerolles, F
Barbat, C
Trucy, M
Kolanus, W
Fischer, A
机构
[1] Hop Necker Enfants Malad, INSERM U429, F-75743 Paris 15, France
[2] Univ Munich, Mol Biol Lab, Gene Ctr, D-81377 Munich, Germany
关键词
D O I
10.1074/jbc.M110064200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have previously shown that CD4 ligand binding inhibits LFA-1-dependent adhesion between CD4+ T cells and B cells in a p56(lck) - and phosphatidylinositol. 3-kinase (PI3-kinase)-dependent manner. In this work, downstream events associated with adhesion inhibition have been investigated. By using HUT78 T cell lines, CD4 ligands were shown to induce a dissociation of LFA-1 from cytohesin, a cytoplasmic protein known to bind LFA-1 and to enhance the affinity/avidity of LFA-1 for its ligand ICAM-1. A dissociation of PI3-kinase from cytohesin is also observed. In parallel, we have found that CD4 ligand binding induced a redistribution of PI3kinase and of the tyrosine phosphatase SHP-2 to the membrane and induced a transient formation of protein interactions including P13-kinase; an adaptor protein, Gab2; SHP-2; and a SH2 domain-containing inositol phosphatase, SHIP. By using antisense oligonucleotides or transfection of transdominant mutants, down-regulation of adhesion was shown to require the Gab2/PI3kinase association and the expression of SHIP and SHP-2. We therefore propose that CD4 ligands, by inducing these molecular associations, lead to sustained local high levels of D-3 phospholipids and possibly regulate the cytohesin/LFA-1 association.
引用
收藏
页码:1276 / 1283
页数:8
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