The catalytic subunit of protein phosphatase 1 gamma regulates thrombin-induced murine platelet alpha(IIb)beta(3) function.
The catalytic subunit of protein phosphatase 1 gamma regulates thrombin-induced murine platelet alpha(IIb)beta(3) function.
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DOI：
10.1371/journal.pone.0008304
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发表时间：
2009-12-15
期刊：
影响因子：
3.7
通讯作者：
Vijayan KV
中科院分区：
文献类型：
--
作者：
Gushiken FC;Hyojeong H;Pradhan S;Langlois KW;Alrehani N;Cruz MA;Rumbaut RE;Vijayan KV
止血和血栓形成是由激动剂诱导的血小板整合素α ib β3的活化调节的。反过来，整合素的激活是通过蛋白激酶和蛋白磷酸酶介导的细胞信号传导。虽然蛋白磷酸酶1 （PP1c）的催化亚基与α ib β3相互作用，但PP1c在血小板反应性中的作用尚不清楚。利用PP1c缺陷小鼠（PP1cγ−/−）的γ异构体，我们发现血小板对低浓度凝血酶或蛋白酶激活受体4 （PAR4）激活肽的可溶性纤维蛋白原结合和聚集适度降低，但对二磷酸腺苷（ADP）、胶原或胶原相关肽（CRP）没有影响。凝血酶刺激的PP1cγ−/−血小板显示αIIbβ3活性降低，尽管αIIbβ3、PAR3、PAR4的表达和正常颗粒分泌水平相当。由外向内整合素α ib β3信号调节的功能，如对固定纤维蛋白原的粘附和凝块缩回，在PP1cγ−/−血小板中没有改变。在PP1cγ−/−小鼠中，光/染料损伤引起的肌小静脉血栓形成明显延迟。促进血小板功能的糖原合成酶激酶(GSK3)β-丝氨酸9的磷酸化在凝血酶刺激的PP1cγ−/−血小板中通过AKT独立的机制降低。抑制GSK3β部分消除了凝血酶刺激的野生型和PP1cγ−/−血小板之间纤维蛋白原结合的差异。这些研究表明PP1cγ在维持凝血酶信号下游的gsk3 β-丝氨酸9磷酸化和通过纤维蛋白原结合和血小板聚集促进血栓形成方面发挥作用。
Hemostasis and thrombosis are regulated by agonist-induced activation of platelet integrin αIIbβ3. Integrin activation, in turn is mediated by cellular signaling via protein kinases and protein phosphatases. Although the catalytic subunit of protein phosphatase 1 (PP1c) interacts with αIIbβ3, the role of PP1c in platelet reactivity is unclear. Using γ isoform of PP1c deficient mice (PP1cγ−/−), we show that the platelets have moderately decreased soluble fibrinogen binding and aggregation to low concentrations of thrombin or protease-activated receptor 4 (PAR4)-activating peptide but not to adenosine diphosphate (ADP), collagen or collagen-related peptide (CRP). Thrombin-stimulated PP1cγ−/− platelets showed decreased αIIbβ3 activation despite comparable levels of αIIbβ3, PAR3, PAR4 expression and normal granule secretion. Functions regulated by outside-in integrin αIIbβ3 signaling like adhesion to immobilized fibrinogen and clot retraction were not altered in PP1cγ−/− platelets. Thrombus formation induced by a light/dye injury in the cremaster muscle venules was significantly delayed in PP1cγ−/− mice. Phosphorylation of glycogen synthase kinase (GSK3)β-serine 9 that promotes platelet function, was reduced in thrombin-stimulated PP1cγ−/− platelets by an AKT independent mechanism. Inhibition of GSK3β partially abolished the difference in fibrinogen binding between thrombin-stimulated wild type and PP1cγ−/− platelets. These studies illustrate a role for PP1cγ in maintaining GSK3β-serine9 phosphorylation downstream of thrombin signaling and promoting thrombus formation via fibrinogen binding and platelet aggregation.
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