A potent inhibitor of endothelial cell proliferation is generated by proteolytic cleavage of the chemokine platelet factor 4.
Platelet factor 4 (PF-4) is an archetype of the "chemokine" family of low molecular weight proteins that play an important role in injury responses and inflammation. From activated human leukocyte culture supernatants, we have isolated a form of PF-4 that acts as a potent inhibitor of endothelial cell proliferation. The PF-4 derivative is generated by peptide bond cleavage between Thr-16 and Ser-17, a site located downstream from the highly conserved and structurally important CXC motif. The unique cleavage leads to a loss of one of the structurally important large loops in the PF-4 molecule and generation of an N terminus with basic residues that have the potential to interact with the acidic extracellular domain of the G-protein-coupled chemokine receptor. The N-terminal processed PF-4 exhibited a 30- to 50-fold greater growth inhibitory activity on endothelial cells than PF-4. Since endothelial cell growth inhibition is the only known cellular activity of the cleaved PF-4, we have designated this chemokine endothelial cell growth inhibitor. The N-terminal processing of PF-4 may represent an important mechanism for modulating PF-4 activity on endothelial cells during tissue injury, inflammation, and neoplasia.
Gupta
S K
SK
Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Hassel
T
T
Singh
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta; D002417:Cattle; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005333:Fetus; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006321:Heart; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000502:physiology*; D008961:Models, Structural; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010978:Platelet Factor 4 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D012694:Serine; D013912:Threonine
D017077:Culture Media, Conditioned; D006131:Growth Inhibitors; D010446:Peptide Fragments; D013912:Threonine; D010978:Platelet Factor 4; D012694:Serine; D004247:DNA