ROLES OF HEPARAN SULFATE PROTEOGLYCANS IN SIGNALING

硫酸乙酰肝素蛋白多糖(HSPGs)由连接在糖胺聚糖链(GAG)上的蛋白核心组成，参与细胞黏附、运动、增殖和分化等多种细胞过程。尽管HSPG代表了细胞表面分子的主要类别之一，但人们对它们的实际作用和特异性知之甚少。最近，HSPG在发育过程和特定信号通路中的关键作用已经通过鉴定与HSPG生物合成有关的一些基因突变而得到阐明。在果蝇中，产生或修改GAG链的酶的突变表现为无翼(Wg)、成纤维细胞生长因子(FGF)和/或Hedgehog(HH)活性的丧失。有趣的是，特定的信号通路似乎被参与Gag链形成的一些酶的突变以及编码蛋白质核心的基因突变所扰乱。我们的假设是，HSPG在配体/受体的相互作用以及细胞外信号的分布中发挥着特定的作用。为了深入了解这些分子在信号传递过程中的功能和特异性，我们将分析参与GAG链生物合成的酶以及Syndecan和Glypicans(Dally和K-glypcan)编码的蛋白质核心的作用。利用遗传学、细胞生物学和生化研究，我们建议：确定HSPG参与HH信号转导的蛋白质核心；阐明参与HH信号转导的HSPG；确定Tout velu/Ext糖基转移酶对HH信号专一性的基础；阐明DALY如何与Wg及其受体Dfz2合作；证明Syndecan编码参与成纤维细胞生长因子信号转导的HSPG；阐明Syndecan如何与Wg及其受体Dfz2合作；证明Syndecan编码参与成纤维细胞生长因子信号转导的HSPG；以及确定合成HSPG的其他酶的特征。总之，我们对HSPGs的分析将阐明HSPGs在许多信号通路中的功能，这些信号通路在发育过程中发挥重要作用。由于这些信号通路也与不同的疾病阶段有关，例如，肿瘤发生，我们的研究可能导致新的方法来调节这些信号通路的活性。

Heparan sulfate proteoglycans (HSPGs), which are composed of a protein core attached to Glycosaminoglycan (GAG) chains, have been implicated in a number of cellular processes such as cell adhesion, motility, proliferation, and differentiation. Although HSPGs represent one of the major classes of cell surface molecules, their actual roles and specificities are poorly understood. Recently, the critical roles of HSPGs in developmental processes and specific signaling pathways have been illustrated by the identification of a number of mutations in genes involved in HSPG biosynthesis. In Drosophila, mutations in enzymes that generate or modify the GAG chains, exhibit phenotypes reminiscent of loss of Wingless (Wg), Fibroblast Growth Factor (FGF) and/or Hedgehog (Hh) activities. Intriguingly, specific signaling pathways appear to be disrupted by mutations in some of the enzymes involved in GAG chain formation, as well as in genes that encode the protein cores. Our hypothesis is that HSPGs play specific roles in ligand/receptor interactions as well as distribution on extra cellular signals. To gain insight into the function and specificity of these molecules during signaling, we will analyze the roles of both the enzymes involved in biosynthesis of the GAG chains, as well as the protein cores encoded by Syndecan and Glypicans (Dally and K-Glypican). Using genetic, cell biological and biochemical studies, we propose to: identify the protein core of the HSPG involved in Hh signaling; elucidate of the HSPG involved in Hh signaling, determine the basis of the specificity of Tout velu/Ext glycosyltransferase to Hh signaling; elucidate how Dally co- operates with Wg and its receptor, Dfz2; demonstrate that Syndecan encodes the HSPG involved in FGF signaling; elucidate how ally co- operates with Wg and its receptor, Dfz2; demonstrate that Syndecan encodes the HSPG involved in FGF signaling; and characterize additional enzymes that synthesize HSPGs. Altogether, our analyses of HSPGs will elucidate the function of HSPGs in a number of signaling pathways that play major roles in developmental processes. Because these pathways have also been implicated in various disease stages; e.g., oncogenesis, our studies may lead to novel ways to modulate specifically the activity of these signaling pathways.