Vlodavsky I, Miao H Q, Medalion B, Danagher P, Ron D
Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Cancer Metastasis Rev. 1996 Jun;15(2):177-86. doi: 10.1007/BF00437470.
Heparan sulfate proteoglycans (HSPGs) are ubiquitous macromolecules associated with the cell surface and extracellular matrix (ECM) of a wide range of cells of vertebrate and invertebrate tissues [1, 2]. The basic HSPG structure consists of a protein core to which several linear heparan sulfate (HS) chains are covalently attached. The polysaccharide chains are typically composed of repeating hexuronic and D-glucosamine disaccharide units that are substituted to a varying extent with N- and O-linked sulfate moieties and N-linked acetyl groups [1, 2]. Beside serving as a scaffold for the attachment of various ECM components (e.g., collagen, laminin, fibronectin), the binding of HS to certain proteins has been suggested to induce a conformational change which may lead to the exposure of novel reactive determinants or conversely stabilize an inert protein configuration [1-4]. Of particular significance is the interaction of HS with fibroblast growth factors (FGFs), mediating their sequestration, stabilization and high affinity receptor binding and signaling [3-7]. Cellular responses to FGFs may hence be modulated by metabolic inhibitors of HS synthesis and sulfation, HS-degrading enzymes, and synthetic mimetics of heparin/HS. In the present review we focus on the involvement of HS in basic FGF (bFGF) receptor binding and mitogenic activity and its modulation by species of heparin, HS, and synthetic polyanionic 'heparin-mimicking' compounds. The results are discussed in relation to the current thoughts on the dual involvement of low and high affinity receptor sites in the growth promoting and angiogenic activities of bFGF and other heparin-binding growth factors.
硫酸乙酰肝素蛋白聚糖（HSPGs）是广泛存在于脊椎动物和无脊椎动物组织的多种细胞的细胞表面和细胞外基质（ECM）中的大分子[1,2]。HSPG的基本结构由一个蛋白核心组成，几条线性硫酸乙酰肝素（HS）链共价连接到该核心上。多糖链通常由重复的己糖醛酸和D-葡糖胺二糖单元组成，这些单元在不同程度上被N-和O-连接的硫酸基团以及N-连接的乙酰基取代[1,2]。除了作为各种ECM成分（如胶原蛋白、层粘连蛋白、纤连蛋白）附着的支架外，HS与某些蛋白质的结合已被认为会诱导构象变化，这可能导致新的反应性决定簇暴露，或者相反地稳定惰性蛋白质构型[1-4]。HS与成纤维细胞生长因子（FGFs）的相互作用尤为重要，它介导FGFs的隔离、稳定以及高亲和力受体结合和信号传导[3-7]。因此，细胞对FGFs的反应可能会受到HS合成和硫酸化的代谢抑制剂、HS降解酶以及肝素/HS的合成模拟物的调节。在本综述中，我们重点关注HS在碱性成纤维细胞生长因子（bFGF）受体结合和促有丝分裂活性中的作用，以及肝素、HS和合成聚阴离子“肝素模拟”化合物对其的调节。我们结合当前关于低亲和力和高亲和力受体位点在bFGF和其他肝素结合生长因子的生长促进和血管生成活性中的双重作用的观点来讨论这些结果。
