REGULATION OF FIBRINOLYSIS BY CELL SURFACES

细胞表面对纤维蛋白溶解的调节

• 批准号: 2218769
• 负责人: Lindsey A Miles
• 金额: $ 23.17万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2218769
• 关键词: animal tissue; antifibrinolytic agents; binding proteins; biological signal transduction; cell adhesion molecules; cell membrane; chemical association; cyclic AMP; enzyme mechanism; enzyme structure; exocytosis; fatty acylation; fibrinolysis; gene expression; human tissue; membrane proteins; molecular site; phosphopyruvate hydratase; plasminogen; plasminogen activator; posttranslational modifications; protein kinase C; protein sequence; receptor expression; secretion

DESCRIPTION (Adapted from the Applicant's Abstract): This is a revised application to investigate the mechanism by which the interaction of plasminogen with specific cellular receptors functions to enhance fibrinolysis. The proposal is based on data establishing that plasminogen interacts with cells in a structurally specific manner, and that this interaction promotes plasminogen activation, and establishes a local nidus of protected plasmin activity. The high capacity of cells for plasminogen suggests that several cell surface molecules may interact with plasminogen. The Applicant has identified a specific subclass of plasminogen receptors with carboxyl terminal lysyl residues that are predominantly responsible for promoting plasminogen activation. She has identified and characterized one member of this subclass, ERM, an alpha-enolase related molecule. ERM exhibits profibrinolytic properties in that it: enhances plasminogen activation, competes for the interaction with the major plasmin inhibitor, a2-antiplasmin and is present on cell surfaces at high capacity. However, despite its localization on the cell surface, it does not have a clearable signal peptide. Hence the first Specific Aim will be to determine whether the alpha-enolase related molecule on the cell surface is structurally distinct from cytoplasmic alpha-enolase, and to test potential mechanisms by which ERM becomes associated with the surface. The Applicant has also noted three additional cell surface proteins which have exposed carboxyl terminal lysyl residues and bind plasminogen. The profibrinolytic function of these proteins will be evaluated in Specific Aim 2, and they will be further characterized, if warranted. In Specific Aim 3, mechanisms of regulation of plasminogen binding site expression will be investigated. The roles of adhesion and specific intracellular signalling pathways in up-regulation of plasminogen receptor expression will be tested, and up-regulation of specific plasminogen receptors will be addressed. Functional consequences of receptor modulation will be also be investigated. Finally, in Specific Aim 4, the Applicant proposes to test the hypothesis that the transition from glu-plasminogen to lys plasminogen is required for the enhancement of plasminogen activation on cell surfaces, and to isolate the cellular enzymes repsonsible for this pro-fibrinolytic activity.

描述（改编自申请人的摘要）：这是一个 修订申请以调查该机制 纤溶酶原与特定细胞受体的相互作用 具有增强纤维蛋白溶解作用。该提案基于数据 确定纤溶酶原与细胞在结构上相互作用 特定方式，并且这种相互作用促进纤溶酶原 激活，并建立受保护的纤溶酶的局部病灶 活动。 细胞对纤溶酶原的高容量表明 一些细胞表面分子可能与纤溶酶原相互作用。 这 申请人已鉴定出纤溶酶原受体的特定亚类 具有羧基末端赖氨酰残基，主要是 负责促进纤溶酶原激活。 她已经确定 并表征了该亚类的一个成员 ERM（一种 α-烯醇酶） 相关分子。 ERM 表现出纤溶酶特性： it：增强纤溶酶原激活，竞争与 主要的纤溶酶抑制剂，a2-抗纤溶酶，存在于细胞上 高容量的表面。然而，尽管其本地化 细胞表面不具有可清除的信号肽。 因此 第一个具体目标是确定 α-烯醇酶是否 细胞表面的相关分子在结构上不同于 细胞质 α-烯醇化酶，并测试 ERM 的潜在机制 与表面相关联。申请人还指出了三点 具有暴露羧基的其他细胞表面蛋白 末端赖氨酰残基并结合纤溶酶原。纤溶原 这些蛋白质的功能将在具体目标 2 中进行评估，并且 如果有必要，将进一步对它们进行表征。特定目标 3、纤溶酶原结合位点的调控机制 表达将被研究。粘附力和作用 特定的细胞内信号通路上调 将测试纤溶酶原受体表达，并上调 将讨论特定的纤溶酶原受体。功能性 还将研究受体调节的后果。 最后，在具体目标 4 中，申请人建议测试 假设从谷氨酰胺纤溶酶原转变为赖氨酸纤溶酶原 是增强细胞纤溶酶原激活所必需的 表面，并分离出对此负责的细胞酶 促纤溶活性。