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 beta 2 integrin-induced protein tyrosine phosphorylations or cytosolic calcium transients. However, AGGC inhibited beta 2 integrin-induced actin polymerization (IC50 of approximately 45nM), as did AFC(IC50 of approximately 5.5 microM), 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.