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-protein s (LMW G-proteins) in beta(2) integrin-dependent neutrophil signal tra nsduction was investigated using two methyltransferase inhibitors, N-A cetyl-S-farnesyl-L-cysteine (AFC) and N-Acetyl-S-geranylgeranyl-L-cyst eine (AGGC), and an inactive control, N-acetyl-S-geranyl-L-cysteine (A GC). The drugs did not affect Bz integrin-induced protein tyrosine pho sphorylations 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, pren ylated proteins, such as LMW G-proteins, are responsible for beta(2) i ntegrin regulation of actin filament reorganization downstream of tyro sine 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.