Ba. Gilbert et al., FARNESYL THIOTRIAZOLE, A POTENT NEUTROPHIL AGONIST AND STRUCTURALLY NOVEL ACTIVATOR OF PROTEIN-KINASE-C, Biochemistry, 34(12), 1995, pp. 3916-3920
Farnesylcysteine derivatives can initiate or inhibit superoxide (O-2(-
)) release in neutrophils. The mechanism by which one of these derivat
ives, farnesyl thiotriazole (FTT), initiates O-2(-) release in neutrop
hils is the subject of this paper. Treatment of guinea pig neutrophils
with FTT results in the rapid release of O-2(-) by a route shown to b
e independent of the chemotactic peptide N-formyl-Met-Leu-Phe (fMLP) r
eceptor. The signal transduction pathway utilized by the chemoattracta
nt fMLP is generally accepted as the paradigm for receptor-mediated st
imulation of O-2(-) production. Antagonists of fMLP had no effect on F
TT-induced O-2(-) release, and pretreatment of neutrophils with fMLP h
ad no effect on the ability of FTT to trigger further O-2(-) generatio
n. In fact, FTT behaves like a typical protein kinase C (PKC) activato
r. It promotes phosphorylation of the 47-kDa subunit of the NADH oxida
se complex (p47-phox) in neutrophils, and this phosphorylation is spec
ifically blocked by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-
7), an antagonist of PKC. FTT is also shown to activate PKC in vitro i
n a specific and saturable fashion. FTT is approximately equipotent wi
th (S)-diolein, a physiologically relevant activator of this kinase. F
TT represents a new, and quite novel, structure for a PKC activator. P
KC activators include diglycerides and the structurally diverse tumor
promoters.