From the School of Physiology, Pharmacology and Neuroscience, University of Bristol, United Kingdom (A.W., C.M.W., E.B., A.W.P.); and KWS Biotest, Portishead, Bristol, United Kingdom (T.I., N.W.).
Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):787-800. doi: 10.1161/ATVBAHA.117.310294. Epub 2018 Feb 8.
RalA and RalB GTPases are important regulators of cell growth, cancer metastasis, and granule secretion. The purpose of this study was to determine the role of Ral GTPases in platelets with the use of platelet-specific gene-knockout mouse models.
This study shows that platelets from double knockout mice, in which both GTPases have been deleted, show markedly diminished (≈85% reduction) P-selectin translocation to the surface membrane, suggesting a critical role in α-granule secretion. Surprisingly, however, there were only minor effects on stimulated release of soluble α- and δ-granule content, with no alteration in granule count, morphology, or content. In addition, their expression was not essential for platelet aggregation or thrombus formation. However, absence of surface P-selectin caused a marked reduction (≈70%) in platelet-leukocyte interactions in blood from RalAB double knockout mice, suggesting a role for platelet Rals in platelet-mediated inflammation.
Platelet Ral GTPases primarily control P-selectin surface expression, in turn regulating platelet-leukocyte interaction. Ral GTPases could therefore be important novel targets for the selective control of platelet-mediated immune cell recruitment and inflammatory disease.
RalA 和 RalB GTPases 是细胞生长、癌症转移和颗粒分泌的重要调节剂。本研究旨在使用血小板特异性基因敲除小鼠模型确定 Ral GTPases 在血小板中的作用。
本研究表明，两种 GTPases 均被删除的双敲除小鼠血小板中，P-选择素向细胞膜表面的转位明显减少（≈85%），表明其在α-颗粒分泌中起关键作用。然而，令人惊讶的是，这对刺激释放可溶性α-和δ-颗粒内容物的影响很小，颗粒计数、形态或含量没有改变。此外，其表达对于血小板聚集或血栓形成不是必需的。然而，表面 P-选择素的缺失导致来自 RalAB 双敲除小鼠血液中的血小板-白细胞相互作用显著减少（≈70%），表明血小板 Ral 在血小板介导的炎症中起作用。
血小板 Ral GTPases 主要控制 P-选择素的表面表达，进而调节血小板-白细胞相互作用。因此，Ral GTPases 可能是选择性控制血小板介导的免疫细胞募集和炎症性疾病的重要新靶点。
