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.
Molony
L
L
Department of Cell Biology, Linköping University, Sweden.
Ng-Sikorski
J
J
Hellberg
C
C
Andersson
T
T
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000199:Actins / Q000187:drug effects / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018821:CD18 Antigens / Q000502:physiology*; D002118:Calcium / Q000097:blood*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D016023:Integrins / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000199:Actins; D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D004224:Diterpenes; D004791:Enzyme Inhibitors; D016023:Integrins; C079500:N-acetyl-S-geranylcysteine; C095716:N-acetyl-S-geranylgeranyl-cysteine; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D003545:Cysteine; C068268:N-acetyl-S-farnesylcysteine; D002118:Calcium; D000111:Acetylcysteine