Integrin-dependent leukocyte adhesion involves geranylgeranylated protein(s)

Integrin-dependent leukocyte adhesion is modulated by alterations in recept or affinity or by post-receptor events. Pretreatment of Jurkat T-cells with the 3-hydroxymethylglutaryl-coenzyme A reductase inhibitor, lovastatin, ma rkedly reduced (IC5- approximate to 1-2 mu M) alpha(4)beta(1)-dependent adh esion to fibronectin (FN) stimulated by phorbol 12-myristate 13-acetate (PM A) which modulates post-receptor events. In contrast, lovastatin did not in hibit Jurkat cell adhesion to FN induced by the beta(1) integrin-activating monoclonal antibody (mAb) 8A2, which directly modulates beta(1) integrin a ffinity. Similarly, pretreatment of U937 cells with lovastatin inhibited PM A-stimulated, but not mAb 8A2-stimulated, alpha(6)beta(1)-dependent leukocy te adhesion to laminin. The inhibition of lovastatin on PMA-stimulated leuk ocyte adhesion was not mediated by mitogen-activated protein kinase or phos phatidylinositol 3-kinase pathway. The inhibitory effect of lovastatin on P MA-stimulated leukocyte adhesion was reversed by co-incubation with geranyl geraniol, but not with farnesol, with concurrent reversal of the inhibition of protein prenylation as shown by protein RhoA geranylgeranylation. The s elective inhibition of protein geranylgeranylation by the specific protein geranylgeranyltransferase-I inhibitor, GGTI-298, blocked PMA-stimulated leu kocyte adhesion but not mAb 8A2-induced leukocyte adhesion. The protein far nesyltransferase inhibitor, FTI-277, had no effect on leukocyte adhesion in duced by either stimulus. These results demonstrate that protein geranylger anylation, but not farnesylation, is required for integrin dependent post-r eceptor events in leukocyte adhesion.