Shattil S J
Division of Hematology-Oncology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0726, USA.
J Thromb Haemost. 2009 Jul;7 Suppl 1:210-3. doi: 10.1111/j.1538-7836.2009.03397.x.
Platelet integrin alphaIIbbeta3 plays an essential role in thrombus formation through interactions with adhesive ligands. Successful parenteral blockade of these interactions has validated alphaIIbbeta3 as a therapeutic target in cardiovascular medicine. However, oral alphaIIbbeta3 antagonists have not been successful and there is an unmet need for more effective anti-platelet drugs. Growing evidence points to the cytoplasmic tails of alphaIIb and beta3, and the beta3 tail in particular, as scaffolds for intracellular proteins that mediate inside-out signaling and regulate alphaIIbbeta3 affinity for ligands. Intracellular protein interactions with the integrin cytoplasmic tails also regulate outside-in signals to the actin cytoskeleton. Here we focus on recent studies that illustrate the relevance of the beta3 cytoplasmic tail as a regulatory scaffold in vivo. We speculate that this scaffold or its interacting proteins may serve as therapeutic targets for the development of future anti-thrombotic drugs.
血小板整合素αIIbβ3通过与黏附配体相互作用在血栓形成中起关键作用。成功地通过肠胃外途径阻断这些相互作用已证实αIIbβ3是心血管医学中的一个治疗靶点。然而，口服αIIbβ3拮抗剂尚未取得成功，因此对更有效的抗血小板药物仍有未满足的需求。越来越多的证据表明，αIIb和β3的细胞质尾巴，尤其是β3尾巴，作为细胞内蛋白质的支架，介导由内向外的信号传导并调节αIIbβ3对配体的亲和力。细胞内蛋白质与整合素细胞质尾巴的相互作用还调节向肌动蛋白细胞骨架的由外向内的信号。在此，我们重点关注最近的研究，这些研究阐明了β3细胞质尾巴作为体内调节支架的相关性。我们推测，这个支架或其相互作用的蛋白质可能作为未来抗血栓药物开发的治疗靶点。
