Integrin-dependent leukocyte adhesion involves geranylgeranylated protein(s).
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 (IC(50) approximately 1-2 microM) alpha(4)beta(1)-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 beta(1) integrin-activating monoclonal antibody (mAb) 8A2, which directly modulates beta(1) integrin affinity. Similarly, pretreatment of U937 cells with lovastatin inhibited PMA-stimulated, but not mAb 8A2-stimulated, alpha(6)beta(1)-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.
Liu
L
L
Division of Hematology, University of Washington, Seattle, Washington 98195, USA. liliu@u.washington.edu
Moesner
P
P
Kovach
N L
NL
Bailey
R
R
Hamilton
A D
AD
Sebti
S M
SM
Harlan
J M
JM
D001549:Benzamides / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D004224:Diterpenes / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000502:physiology*; D019169:Jurkat Cells; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D020298:U937 Cells
D001549:Benzamides; D004224:Diterpenes; C096856:FTI 277; D005353:Fibronectins; C102521:GGTI 298; D016023:Integrins; D008148:Lovastatin; D008715:Methionine; C017338:geranylgeraniol; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate