FGF SIGNALLING BY CELL SURFACE PROTEOGLYCANS

成纤维细胞生长因子（FGF）调节一系列生理和病理变化。 病理过程。促进细胞生长和分化 在来自所有三个胚胎胚层的组织中发现的类型， 介导细胞胚胎发育的方面（例如，肌肉和神经 发育）血管生成。细胞运动性，并且还显著地 调节各种肿瘤的发展。FGF诱导细胞 通过结合和激活细胞表面FGF受体酪氨酸的反应 激酶（FGFR 1-4）。启动特定的信号转导途径 在受体活化后导致多种细胞反应。细胞 表面硫酸乙酰肝素蛋白聚糖（HSPG促进FGF/FGFR 交互.存在几类HSPG;其中两类是 多配体蛋白聚糖（Synds 1-4）、整合膜HSPG和脂质连接HSPG 如葡聚糖（CBG）。这两种形式都是实验的重点 在这里提出。两种形式都结合FGF，但锚定方式不同， 表明对FGF的不同反应受到调节， 通过该形式介导FGF/FGFr相互作用。本研究的目的是 为了阐明HSPGs在介导FGF信号传导中的作用， 细胞表达单一HSPG沿着单一FGF的问题 受体类型具体目的是：1）确定可溶性Synd 1或CBG 在FGFR阳性/HSPG中，它们介导FGF信号传导的能力不同 阴性细胞; 2）确定细胞表面锚定的Synd 1或CBG是否共- 在淋巴样细胞系中以单一类型的FGFR表达， 缺乏这些分子在促进FGF结合的能力上不同 3）评估调节细胞增殖和/或活化FGFR的作用， Synd 1或CBG的表面水平抑制FGF结合和/或 FGF应答细胞中FGFR的活化，和4）检查 Synd 1和CBG介导不同FGF/FGFR信号的激活 FGF应答细胞中的转导途径。

Fibroblast growth factors (FGFs) regulate a range of physiological and pathological processes. They promote growth and differentiation of cell types found in tissues derived from all three embryonic germ layers and mediate aspects of cell embryonic development (e.g., muscle and nerve development) angiogenesis. cell motility, and also function significantly in regulating development of various tumor types. FGFs elicit cellular responses by binding and activating cell surface FGF receptor tyrosine kinases (FGFRs 1-4). Specific signal transduction pathways are initiated upon receptor activation leading to a variety of cellular responses. Cell surface heparan sulfate proteoglycans (HSPGs facilitate FGF/FGFR interactions. Several classes of HSPG exist; two of these are the syndecans (Synds 1-4), integral membrane HSPGs, and lipid-linked HSPGs such as cerebroglycan (CBG). Both forms are the focus of the experiments proposed here. Both forms bind FGF, but the different means of anchoring to the cell surface suggest that different responses to FGFs are regulated by which form mediates FGF/FGFr interactions. The goal of this research is to clarify the role that HSPGs play in mediating FGF signaling by asking questions of a cell expressing a single HSPG along with a single FGF receptor type. The specific aims are 1) determine if soluble Synd1 or CBG differ in their ability to mediate FGF signaling in FGFR positive/HSPG negative cells; 2) determine if cell surface anchored Synd1 or CBG co- expressed with a single type of FGFR in a lymphoid cell line normally devoid of these molecules differ in their ability to promote FGF binding to and/or activation of the FGFR: 3) assess the effects of modulating cell surface levels of Synd1 or CBG in inhibiting FGF binding to and/or activation of the FGFR in FGF responsive cells and 4) examine the ability of Synd1 and CBG to mediate activation of different FGF/FGFR signal transduction pathways in FGF responsive cells.