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J Biol Chem, Vol. 274, Issue 47, 33334-33340, November 19, 1999

Integrin-dependent Leukocyte Adhesion Involves Geranylgeranylated Protein(s)

Li Liu, Patty Moesner, Nicholas L. Kovach, Ratna Bailey, Andrew D. Hamilton^¶, Said M. Sebti, and John M. Harlan

From the  Division of Hematology, University of Washington, Seattle, Washington 98195, the ^¶ Department of Chemistry, Yale University, New Haven, Connecticut 06520, and the  Drug Discovery Program, Department of Biochemistry and Molecular Biology, H. Lee Moffitt Cancer Center & Research Institute, the University of South Florida, Tampa, Florida 33612-9497

Integrin-dependent leukocyte adhesion is modulated by alterations in receptor affinity or by post-receptor events. Pretreatment of Jurkat T-cells with the 3-hydroxymethylglutaryl-coenzyme A reductase inhibitor, lovastatin, markedly reduced (IC₅₀ 1-2 µM) ₄₁-dependent adhesion to fibronectin (FN) stimulated by phorbol 12-myristate 13-acetate (PMA) which modulates post-receptor events. In contrast, lovastatin did not inhibit Jurkat cell adhesion to FN induced by the ₁ integrin-activating monoclonal antibody (mAb) 8A2, which directly modulates ₁ integrin affinity. Similarly, pretreatment of U937 cells with lovastatin inhibited PMA-stimulated, but not mAb 8A2-stimulated, ₆₁-dependent leukocyte adhesion to laminin. The inhibition of lovastatin on PMA-stimulated leukocyte adhesion was not mediated by mitogen-activated protein kinase or phosphatidylinositol 3-kinase pathway. The inhibitory effect of lovastatin on PMA-stimulated leukocyte adhesion was reversed by co-incubation with geranylgeraniol, but not with farnesol, with concurrent reversal of the inhibition of protein prenylation as shown by protein RhoA geranylgeranylation. The selective inhibition of protein geranylgeranylation by the specific protein geranylgeranyltransferase-I inhibitor, GGTI-298, blocked PMA-stimulated leukocyte adhesion but not mAb 8A2-induced leukocyte adhesion. The protein farnesyltransferase inhibitor, FTI-277, had no effect on leukocyte adhesion induced by either stimulus. These results demonstrate that protein geranylgeranylation, but not farnesylation, is required for integrin-dependent post-receptor events in leukocyte adhesion.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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