HEPARAN SULFATE AND FGF ACTION

硫酸乙酰肝素和 FGF 作用

• 批准号: 2186355
• 负责人: ALAN C RAPRAEGER
• 金额: $ 21.71万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2186355
• 关键词: antisense nucleic acid; biological signal transduction; fibroblast growth factor; growth factor receptors; heparan sulfate; laboratory rabbit; protein tyrosine kinase; proteoglycan; receptor binding; site directed mutagenesis; transfection

The heparin binding growth factors (fibroblast growth factor or FGFs) are a family of polypeptides that regulate a variety of cellular behaviors, including cell proliferation, migration and shape change, and cellular determination and differentiation. The diversity of these responses suggests intricate signalling mechanisms. One of the intricacies that will be studied here is the requirement for two types of FGF binding molecules to collaborate at the cell surface in order for FGF signalling to be carried out. One molecule is a membrane-spanning receptor with a cytoplasmic tyrosine-kinase domain that is activated upon ligand binding. The second molecule is a heparan sulfate proteoglycan that binds FGF via its heparan sulfate chains. This latter class of molecules is typified by syndecan, a transmembrane protein. Several other proteoglycans of this general type have been described. A contrasting form of cell surface proteoglycan is glypican, which is tethered to the membrane by a lipid tail. The aim of this work will be to understand the biochemistry of how these types of proteoglycans interact with the tyrosine kinase receptors in order to regulate FGF binding and signalling. Potential regulatory mechanisms include (i) the specific structure of the heparan sulfate chains, which are known to exhibit widely differing affinities for the growth factor, affinities that may vary between the two types of proteoglycans and are expected to vary among cell types and (ii) the nature of the proteoglycan anchorage in the membrane, which may be a critical regulator in the formation of an active complex between the proteoglycan, the receptor and the FGF. These regulatory mechanisms will be studied using two well-defined system: (i) a lymphoid cell expressing a single FGF receptors or receptors and proteoglycans expressed as pairs, and (ii) a myoblast cell line that responds quantitatively to FGF. The lymphoid cells will provide valuable information on ow a single type of receptor interacts with a single type of proteoglycan. The myoblast will provide the means for verifying the role of the interaction in FGF signalling. The potent role of the FGFs in cell growth and differentiation makes them obvious candidates for defects that lead to human disease, particularly in cancer, birth defects and neuromuscular degenerative disorders. Specific examples include their induction of mammary carcinomas, role in sarcoma growth or role as a tumor angiogenic factor. A better understanding of how FGF action is regulated in these diseases will provide insights into potential treatments.

肝素结合生长因子（成纤维细胞生长因子或FGF）是 一个调节各种细胞行为的多肽家族， 包括细胞增殖，迁移和形状变化以及细胞 决心和分化。 这些回应的多样性 提出复杂的信号传导机制。 一个复杂的 将在此研究是两种类型的FGF绑定的要求 分子在细胞表面进行协作以进行FGF信号传导 进行。一个分子是跨膜受体 在配体结合时激活的细胞质酪氨酸激酶结构域。 第二个分子是硫酸乙酰肝素蛋白聚糖，该蛋白聚糖结合FGF通过 它的硫酸乙酰肝素链。 后一种分子是典型的 由Syndecan，一种跨膜蛋白。 其他几个蛋白聚糖 已经描述了这种一般类型。 一种对比形式的细胞形式 表面蛋白聚糖是Glypican，它通过 脂质尾巴。 这项工作的目的是了解 这些类型的蛋白聚糖如何与 酪氨酸激酶受体，以调节FGF结合和 信号。 潜在的调节机制包括（i）特定的 硫酸乙酰肝素链的结构，已知显示 对生长因素的亲和力有很大差异，可能的亲和力可能 两种类型的蛋白聚糖之间有所不同，预计将变化 在细胞类型中，（ii）蛋白聚糖锚固的性质 膜，这可能是活跃形成的关键调节剂 蛋白聚糖，受体和FGF之间的复杂性。 这些 调节机制将使用两个定义明确的系统进行研究：（i） 表达单个FGF受体或受体的淋巴细胞，以及 蛋白聚糖以对表示，（ii）一个成肌细胞系 对FGF进行定量响应。 淋巴细胞将提供有价值的 有关OW单一类型受体的信息与单一类型相互作用 蛋白聚糖。 肌细胞将提供验证的手段 相互作用在FGF信号传导中的作用。 FGF的有力作用 在细胞生长和分化方面使它们显而易见 导致人类疾病的缺陷，特别是在癌症中，出生缺陷 和神经肌肉退化性疾病。 具体示例包括 他们诱导乳腺癌，在肉瘤生长中的作用或 肿瘤血管生成因子。 更好地了解FGF行动的方式 在这些疾病中受到的监管将提供潜在的见解 治疗。