Inhibitors of farnesyl and geranylgeranyl methyltransferases prevent beta(2) integrin-induced actin polymerization without affecting beta(2) integrin-induced Ca2+ signaling in neutrophils

The role of prenylated proteins such as low molecular weight G-proteins (LMW G-proteins) in beta(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 Bz integrin-induced protein tyrosine phosphorylations or cytosolic calcium transients. However, AGGC inhibited beta(2) integrin-induced actin polymerization (IC50 of similar to 45 nM), as did AFC (IC50 of similar to 5.5 mu M), but not AGC. Thus, prenylated proteins, such as LMW G-proteins, are responsible for beta(2) integrin regulation of actin filament reorganization downstream of tyrosine kinase(s) activation, and represent a beta(2) integrin signaling mechanism distinct from the pathway which regulates cytosolic calcium transients. (C) 1996 Academic Press, Inc.