ROLES OF HEPARAN SULFATE PROTEOGLYCANS IN SIGNALING

硫酸乙酰肝素蛋白聚糖（HSPGs）是由一个连接到糖胺聚糖（GAG）链上的蛋白核组成的，它参与了许多细胞过程，如细胞粘附、运动、增殖和分化。虽然HSPGs代表了细胞表面分子的主要类别之一，但它们的实际作用和特异性却知之甚少。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一些参与HSPG生物合成的基因突变得到了阐明。在果蝇中，产生或修饰GAG链的酶发生突变，表现出无翼（Wg）、成纤维细胞生长因子（FGF）和/或Hedgehog （Hh）活性丧失的表型。有趣的是，特定的信号通路似乎被一些参与GAG链形成的酶以及编码蛋白质核心的基因的突变所破坏。我们的假设是HSPGs在配体/受体相互作用以及细胞外信号的分布中发挥特定作用。为了深入了解这些分子在信号传导过程中的功能和特异性，我们将分析这两种酶在GAG链生物合成中的作用，以及Syndecan和Glypicans （Dally和k - Glypicans）编码的蛋白核心。通过遗传学、细胞生物学和生物化学的研究，我们建议：鉴定参与Hh信号传导的HSPG蛋白核心；阐明HSPG参与Hh信号转导，确定Tout velu/Ext糖基转移酶对Hh信号转导特异性的基础；阐明Dally如何与Wg及其受体Dfz2协同作用；证明Syndecan编码参与FGF信号传导的HSPG；阐明ally如何与Wg及其受体Dfz2协同作用；证明Syndecan编码参与FGF信号传导的HSPG；并描述了合成HSPGs的其他酶。总之，我们对hspg的分析将阐明hspg在发育过程中发挥重要作用的许多信号通路中的功能。因为这些途径也与不同的疾病阶段有关；例如，肿瘤发生，我们的研究可能会导致新的方法来调节这些信号通路的活动。

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.