Inhibitors of Farnesyl and Geranylgeranyl Methyltransferases Prevent β2Integrin-Induced Actin Polymerization without Affecting β2Integrin-Induced Ca2+Signaling in Neutrophils

Abstract The role of prenylated proteins such as low molecular weight G-proteins (LMW G-proteins) in β 2 integrin-dependent neutrophil signal transduction was investigated using two methyltransferase inhibitors, N-Acetyl-S-farnesyl-L-cysteine (AFC) and N-Acetyl-S-geranylgeranyl-L-cysteine (AGGC), and an inactive control, N-acetyl-S-geranyl-L-cysteine (AGC). The drugs did not affect β 2 integrin-induced protein tyrosine phosphorylations or cytosolic calcium transients. However, AGGC inhibited β 2 integrin-induced actin polymerization (IC 50 of ∼45nM), as did AFC (IC 50 of ∼5.5 μM), but not AGC. Thus, prenylated proteins, such as LMW G-proteins, are responsible for β 2 integrin regulation of actin filament reorganization downstream of tyrosine kinase(s) activation, and represent a β 2 integrin signaling mechanism distinct from the pathway which regulates cytosolic calcium transients.