Gupta S K, Hassel T, Singh J P
Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7799-803. doi: 10.1073/pnas.92.17.7799.
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.
血小板因子4（PF-4）是低分子量蛋白质“趋化因子”家族的典型代表，这些蛋白质在损伤反应和炎症中起重要作用。从活化的人白细胞培养上清液中，我们分离出一种PF-4形式，它可作为内皮细胞增殖的有效抑制剂。PF-4衍生物是由苏氨酸-16和丝氨酸-17之间的肽键断裂产生的，该位点位于高度保守且结构重要的CXC基序下游。这种独特的切割导致PF-4分子中一个结构重要的大环缺失，并产生一个带有碱性残基的N端，这些碱性残基有可能与G蛋白偶联趋化因子受体的酸性细胞外结构域相互作用。N端加工后的PF-4对内皮细胞的生长抑制活性比PF-4高30至50倍。由于内皮细胞生长抑制是已知的切割后PF-4唯一的细胞活性，我们将这种趋化因子命名为内皮细胞生长抑制剂。PF-4的N端加工可能是在组织损伤、炎症和肿瘤形成过程中调节PF-4对内皮细胞活性的重要机制。
