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β 2 Integrin (CD11/CD18)‐mediated signaling involves tyrosine phosphorylation of c‐Cbl in human neutrophils
Author(s) -
Willeke Thomas,
Behrens Sandra,
ScharffetterKochanek Karin,
Gaehtgens Peter,
Walzog Barbara
Publication year - 2000
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.68.2.284
Subject(s) - integrin , tyrosine phosphorylation , cd18 , integrin alpha m , biology , microbiology and biotechnology , phosphorylation , cd49c , signal transduction , cell adhesion , integrin, beta 6 , collagen receptor , tyrosine , cell adhesion molecule , biochemistry , receptor , cell
Leukocyte adhesion molecules of the β 2 integrin (CD11/CD18) family mediate cell‐cell and cell‐substrate interactions of human polymorphonuclear neutrophils (PMN) during their recruitment to sites of inflammation. To elucidate the molecular events that follow extracellular ligand interactions of β 2 integrins, protein tyrosine signaling was studied subsequent to integrin engagement by Western blotting technique. Upon adhesion to immobilized fibrinogen, a native ligand of the β 2 integrins Mac‐1 (CD11b/CD18) and gp150/95 (CD11c/CD18), tyrosine phosphorylation of several proteins including a 120‐kDa protein was observed in human PMN. This effect was specific for β 2 integrins because it was absent in PMN derived from CD18‐deficient mice, which lack any β 2 integrin expression. Moreover, no signaling was detectable upon engagement of CD29 and CD61, the β‐subunits of the β 1 and β 3 integrins, respectively, revealing the unique function of the β 2 integrins in PMN. By means of immunoprecipitation, the most prominent protein that became tyrosine phosphorylated upon β 2 integrin engagement was identified as the 120‐kDa protein c‐Cbl. The observed signaling was independent of both pertussis toxin‐sensitive heterotrimeric G‐proteins as well as the small G‐protein ras. Inhibition of β 2 integrin‐mediated signaling by herbimycin A prevented adhesion, shape change, and spreading of PMN to immobilized fibrinogen, demonstrating the biological significance of the observed effect. Together, the present data suggest that the β 2 integrins fulfill a unique function among the leukocyte integrins in human PMN by activating an intracellular signal transduction cascade that leads to tyrosine phosphorylation of c‐Cbl and allows subsequent adhesion, shape change, and spreading.