Outside-in signaling mechanisms of platelet integrin alpha-IIb-beta3

血小板整合素α-IIb-β3由外而内的信号传导机制

基本信息

批准号：
9241429
负责人：
Xiaoping Du
金额：
$ 40.35万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241429
关键词：
Adhesions Adhesives Adverse effects Affect Agonist Alpha Granule Arteries Binding Binding Sites Blood Platelets Blood Vessels Clot retraction Coagulation Process Cytoplasmic Granules Cytoplasmic Tail Data Development Disease Dissociation Fibrin Fibrinogen Fibrinolytic Agents Funding Future GTP-Binding Proteins Generations Hemorrhage Hemostatic function Injury Integrin Inhibition Integrin beta Chains Integrin beta3 Integrins Life Ligand Binding Ligands Mediating Myocardial Infarction Outcome Pathologic Pharmaceutical Preparations Phase Physiological Platelet Activation Platelet Membrane Glycoprotein IIb Play Protein Subunits Regulation Role SRC gene Signal Pathway Signal Transduction Site Stroke Talin Testing Thrombosis Thrombus Time Tyrosine Phosphorylation adhesion receptor base extracellular improved inhibitor/antagonist new therapeutic target prevent public health relevance response

项目摘要

DESCRIPTION (provided by applicant): The platelet adhesion receptor, integrin αIIbβ3, plays a critical physiological role in hemostasis and also a critical pathological role in thrombosis and in the development of thrombotic diseases such as heart attack and stroke. The integrin antagonists are effective anti-thrombotics but also have significant adverse effect of hemorrhage, which can be life-threatening. Thus, it is important to develop a new generation of anti-thrombotics that minimally cause adverse effect of bleeding. Integrin αIIbβ3 not only mediates platelet adhesion and aggregation but also transmits signals bidirectionally: Agonist-induced intracellular signals from within platelets activate the extracellular ligand binding function of integrin αIIbβ3 ("inside-out" signaling). The binding of extracellular ligand to αIIβ3 then induces "outside-in" signals, which elicit cellular responses such as platelet spreading, granule secretion, and platelet-dependent clot retraction. The "outside-in signaling" response is critical in amplifying and stabilizing thrombi, which is critically important in occlusive thromboss. During the current funding period, we have shown that the G protein subunit, Gα13, directly interacts with a highly conserved ExE motif in the cytoplasmic domain of several integrin β subunits between talin binding sites, and "time-share" the binding region with talin in opposing waves. Talin binding occurs during inside-out signaling and late phase outside-in signaling, whereas the Gα13 binding occurs during early phase outside-in signaling. We further show that Gα13 is selectively important in the early phase outside-in signaling leading to platelet spreading and amplification of platelet thrombus formation. Importantly, we have developed selective inhibitors of Gα13-integrin interaction that potently inhibited integrin outside-in signaling and arterial thrombosis without causing adverse effect of bleeding. Based on these data, we propose the overall hypothesis that the opposing waves of talin and Gα13 binding to integrin cytoplasmic domain switch the direction of integrin signaling and also control outcomes of integrin outside-in signaling. To test this hypothesis, we propose the following specific aims: (1) To investigate the switch between talin and Gα13 binding to β3 during integrin signaling and its regulatory mechanisms. (2)To further investigate the roles of Gα13-integrin interaction in mediating integrin outside-in signaling, amplification of platelet activation, and thrombosis. These studies will facilitate the development of new generations of anti-thrombotic drugs for treating thrombosis without causing excessive bleeding.

描述（由应用提供）：血小板粘合剂受体，整联蛋白αIIBβ3在止血中起关键的生理作用，并且在血栓形成和血栓形成中起关键的病理作用在发展血栓形成疾病（如心脏病发作和中风）中。整联蛋白的拮抗剂是有效的抗脉动，但也会对出血的严重不利影响，这可能是威胁生命的。这是重要的是开发新一代的抗脉动学，从而最少会导致出血的不利影响。整联蛋白αIIBβ3不仅介导了血小板广告和聚集，而且在双向上传输信号：来自血小板内部的激动剂诱导的细胞内信号激活了整合素αIIBβ3的细胞外配体结合功能（“内部输出”信号传导）。细胞外配体与αIIβ3的结合会影响“外部”信号，从而引起细胞反应，例如血小板扩散，颗粒分泌和血小板依赖性克隆回收。 “外部信号传导”响应对于放大和稳定血栓至关重要，这在闭合的血栓上至关重要。在当前的资金期间，我们表明，G蛋白亚基Gα13直接与塔林结合位点之间几个整合素β亚基的高度组成的EXE基序相互作用，而在相对波中，与塔林的结合区域“ Time-Share”与“ Time-Share”之间相互作用。塔林结合发生在内而外的信号传导和晚期外部信号传导期间发生，而Gα13结合发生在早期阶段外部信号传导中。我们进一步表明，Gα13在外部信号的早期信号传导中有选择地重要，导致血小板扩散和血小板形成的扩增。重要的是，我们已经开发了Gα13-整合素相互作用的选择性抑制剂，这些抑制剂可能会抑制整联蛋白的外部信号传导和动脉血栓形成，而不会引起出血的不良影响。基于这些数据，我们提出了一个总体假设，即塔林和Gα13的相对波与整合素细胞质结构域结合切换整联蛋白信号传导的方向，并控制整合素外部信号传导的结果。为了检验这一假设，我们提出了以下特定目的：（1）在整合素信号传导及其调节机制期间研究塔林和Gα13与β3的切换。（2）进一步研究Gα13-整合蛋白相互作用在介导整联蛋白外部信号传导，血小板激活的扩增和血栓形成中的作用。这些研究将促进新一代的抗癌症药物来治疗血栓形成，而不会导致过多的出血。