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A directional switch of integrin signalling and a new anti-thrombotic strategy

机译：整合素信号的方向转换和新的抗血栓形成策略

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摘要

Integrins have a critical role in thrombosis and haemostasis. Antagonists of the platelet integrin α_(Ⅱb)β_3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding. It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally. Inside-out signalling activates integrins through a talin-dependent mechanism. Integrin ligation mediates thrombus formation and outside-in signalling, which requires Gα+(13) and greatly expands thrombi. Here we show that Gα_(13) and talin bind to mutually exclusive but distinct sites within the integrin β_3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand-induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and Gα_(13) binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of Gα_(13)-integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding.%整联蛋白是细胞粘附分子，通过双向传输信号来调节由内向外和由外向内的信号作用。"胞质域"与细胞内分子如细胞骨架蛋白talin和G α_(13)相互作用。在这项研究中，Xiaoping Du及 同事发现，信号作用方向可以被talin和Gα_(13)的协调的、相反的"结合波"(binding wave)向具有截然不同识别主题的整联蛋白"胞质域" 的相同区域切换和传输。作者还设计了一种抑制分子，它选择性地以由外向内的信号作用为目标。这种分子在活体中抑制血栓，但又不会造成出血的副作用。
机译：整联蛋白在血栓形成和止血中起关键作用。血小板整联蛋白α_（Ⅱb）β_3的拮抗剂是有效的抗血栓形成药物，但也具有致命的引起出血的不良反应。因此，需要开发不会引起出血的新拮抗剂。整合素双向传输信号。由内而外的信号传导通过塔林依赖性机制激活整合素。整联蛋白连接介导血栓形成和由外而内的信号传导，这需要Gα+（13）并大大扩展血栓。在这里，我们显示Gα_（13）和塔林结合在互斥波中整联蛋白β_3胞质域内的互斥但截然不同的位点。第一个塔林蛋白结合波介导了由内而外的信号传导，也介导了配体诱导的整联蛋白激活，但从外而内的信号传导并不需要。整联蛋白连接诱导短暂的塔林蛋白解离和Gα_（13）与EXE基序（其中X表示任何残基）的结合，后者选择性地介导了由内而外的信号传导和血小板扩散。第二个塔林结合波与血凝块收缩有关。基于EXE基序的Gα_（13）-整合素相互作用抑制剂可在不影响整合素结扎的情况下有选择地消除由内而外的信号传导，并在不影响出血时间的情况下抑制闭塞性动脉血栓形成。因此，我们发现了整合素信号转导的新机制，并在此机制的基础上设计了一种不会引起出血的强效抗栓药物。 “胞质域”与细胞内分子如细胞骨架蛋白talin和Gα_（13）相互作用。在研究中，Xiaoping Du＆同事发现，信号作用方向可以被talin和Gα_（13）的协调的，相反的“结合波”（binding wave）向具有截然不同识别主题的整联蛋白“胞质域”的相同区域切换和传输。了一种抑制分子，它选择性地以由外向内的信号作用为目标。这种分子在活体中抑制血栓，但又不会造成出血的并发症。

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  • 来源
    《Nature》 |2013年第7474期|131-135A2|共6页
  • 作者

    Bo Shen; Xiaojuan Zhao; Kelly A. OBrien; Aleksandra Stojanovic-Terpo; M. Keegan Delaney; Kyungho Kim; Jaehyung Cho; Stephen C.-T. Lam; Xiaoping Du;

  • 作者单位

    Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA;

    Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA;

    Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA;

    Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA;

    Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA;

    Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA;

    Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA;

    Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA;

    Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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