Brown K J, Parish C R
Division of Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra.
Biochemistry. 1994 Nov 22;33(46):13918-27. doi: 10.1021/bi00250a047.
Recent studies have shown that fibroblast growth factors (FGFs) need to interact with cell-surface heparan sulfate proteoglycans (HSPGs) in order to bind to and activate FGF receptors. In this paper, three major heparin-binding proteins, histidine-rich glycoprotein (HRG) and antithrombin III (ATIII), which are constitutively present at high concentrations in plasma, and platelet factor 4 (PF4), which is released locally at high concentrations by degranulating platelets, were tested for their ability to act as modulators of FGF activity by competing with the FGFs for cell-surface HSPGs. HRGs from both chicken and human, and human PF4, were demonstrated to compete with each other and with acidic FGF (aFGF) and basic FGF (bFGF) for binding to BALB/c 3T3 cell-surface HSPGs, whereas ATIII did not compete. Thus, HRG, PF4, aFGF, and bFGF all interact with the same HS chains on the 3T3 cell surface, either binding to the same or binding to adjacent saccharide sequences on the chains. In terms of their relative binding affinity for cell-surface HSPGs, the hierarchy was shown to be PF4 > or = bFGF > aFGF = cHRG > hHRG. HRG was also shown to significantly inhibit both FGF-stimulated and endogenous 3T3 cell DNA synthesis. HRG also binds to extracellular matrices (ECM), originating from bovine corneal endothelial cells, in a heparin-inhibitable manner. Indeed, both HRG and PF4, at physiological concentrations, were shown to effectively inhibit the binding of 125I-aFGF and 125I-bFGF to ECM. In addition, HRG was able to displace biologically active bFGF from the ECM. On the basis of these findings, it is proposed that HRG and PF4 may act as positive regulators of FGF activity by displacing FGF from the ECM or basement membrane and making FGF available to responsive cells. Alternatively, they could act as negative regulators by masking HSPGs on responsive cells and preventing FGF receptor activation.
最近的研究表明，成纤维细胞生长因子（FGFs）需要与细胞表面硫酸乙酰肝素蛋白聚糖（HSPGs）相互作用，才能结合并激活FGF受体。在本文中，检测了三种主要的肝素结合蛋白，即血浆中持续高浓度存在的富含组氨酸糖蛋白（HRG）和抗凝血酶III（ATIII），以及由脱颗粒血小板局部高浓度释放的血小板因子4（PF4），通过与FGF竞争细胞表面HSPGs来调节FGF活性的能力。鸡和人的HRG以及人PF4均被证明可相互竞争，并与酸性FGF（aFGF）和碱性FGF（bFGF）竞争结合BALB/c 3T3细胞表面的HSPGs，而ATIII则不参与竞争。因此，HRG、PF4、aFGF和bFGF均与3T3细胞表面相同的HS链相互作用，要么结合到链上相同的糖序列，要么结合到相邻的糖序列。就它们对细胞表面HSPGs的相对结合亲和力而言，顺序为PF4>或=bFGF>aFGF=cHRG>hHRG。HRG还被证明能显著抑制FGF刺激的和内源性的3T3细胞DNA合成。HRG还以肝素可抑制的方式结合源自牛角膜内皮细胞的细胞外基质（ECM）。实际上，在生理浓度下，HRG和PF4均被证明能有效抑制125I-aFGF和125I-bFGF与ECM的结合。此外，HRG能够从ECM中置换出具有生物活性的bFGF。基于这些发现，有人提出HRG和PF4可能通过从ECM或基底膜上置换FGF并使其可被反应性细胞利用，从而作为FGF活性的正调节因子。或者，它们可能通过掩盖反应性细胞上的HSPGs并阻止FGF受体激活而作为负调节因子。
