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(Journal of Leukocyte Biology. 2000;68:284-292.)
© 2000 by Society for Leukocyte Biology

ß₂ Integrin (CD11/CD18)-mediated signaling involves tyrosine phosphorylation of c-Cbl in human neutrophils

Department of Physiology, Freie Universität Berlin; and
^* Department of Dermatology, Universität zu Köln, Germany

Correspondence: Barbara Walzog, Ph.D., Freie Universität Berlin, Department of Physiology, Arnimallee 22, D-14195 Berlin, Germany.

Leukocyte adhesion molecules of the ß₂ 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 ß₂ integrins, protein tyrosine signaling was studied subsequent to integrin engagement by Western blotting technique. Upon adhesion to immobilized fibrinogen, a native ligand of the ß₂ 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 ß₂ integrins because it was absent in PMN derived from CD18-deficient mice, which lack any ß₂ integrin expression. Moreover, no signaling was detectable upon engagement of CD29 and CD61, the ß-subunits of the ß₁ and ß₃ integrins, respectively, revealing the unique function of the ß₂ integrins in PMN. By means of immunoprecipitation, the most prominent protein that became tyrosine phosphorylated upon ß₂ 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 ß₂ 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 ß₂ 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.

Key Words: adhesion • host defense • inflammation • polymorphonuclear neutrophils

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