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首页> 外文期刊>Molecular and Cellular Biology >LAT Is Required for Tyrosine Phosphorylation of Phospholipase Cγ2 and Platelet Activation by the Collagen Receptor GPVI
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LAT Is Required for Tyrosine Phosphorylation of Phospholipase Cγ2 and Platelet Activation by the Collagen Receptor GPVI

机译：LAT是磷酸酶Cγ2酪氨酸磷酸化和胶原受体GPVI活化血小板所必需的

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In the present study, we have addressed the role of the linker for activation of T cells (LAT) in the regulation of phospholipase Cγ2 (PLCγ2) by the platelet collagen receptor glycoprotein VI (GPVI). LAT is tyrosine phosphorylated in human platelets heavily in response to collagen, collagen-related peptide (CRP), and FcγRIIA cross-linking but only weakly in response to the G-protein-receptor-coupled agonist thrombin. LAT tyrosine phosphorylation is abolished in CRP-stimulated Syk-deficient mouse platelets, whereas it is not altered in SLP-76-deficient mice or Btk-deficient X-linked agammaglobulinemia (XLA) human platelets. Using mice engineered to lack the adapter LAT, we showed that tyrosine phosphorylation of Syk and Btk in response to CRP was maintained in LAT-deficient platelets whereas phosphorylation of SLP-76 was slightly impaired. In contrast, tyrosine phosphorylation of PLCγ2 was substantially reduced in LAT-deficient platelets but was not completely inhibited. The reduction in phosphorylation of PLCγ2 was associated with marked inhibition of formation of phosphatidic acid, a metabolite of 1,2-diacylglycerol, phosphorylation of pleckstrin, a substrate of protein kinase C, and expression of P-selectin in response to CRP, whereas these parameters were not altered in response to thrombin. Activation of the fibrinogen receptor integrin αIIbβ3 in response to CRP was also reduced in LAT-deficient platelets but was not completely inhibited. These results demonstrate that LAT tyrosine phosphorylation occurs downstream of Syk and is independent of the adapter SLP-76, and they establish a major role for LAT in the phosphorylation and activation of PLCγ2, leading to downstream responses such as α-granule secretion and activation of integrin αIIbβ3. The results further demonstrate that the major pathway of tyrosine phosphorylation of SLP-76 is independent of LAT and that there is a minor, LAT-independent pathway of tyrosine phosphorylation of PLCγ2. We propose a model in which LAT and SLP-76 are required for PLCγ2 phosphorylation but are regulated through independent pathways downstream of Syk.
机译：在本研究中，我们已经解决了血小板活化胶原蛋白糖蛋白VI（GPVI）对T细胞活化（LAT）的连接子在磷脂酶Cγ2（PLCγ2）调节中的作用。在胶原蛋白，胶原蛋白相关肽（CRP）和FcγRIIA交联中，LAT在人的血小板中被磷酸化程度很高，但在与G蛋白受体偶联的激动剂凝血酶反应中却很弱。在CRP刺激的Syk缺陷型小鼠血小板中，LAT酪氨酸磷酸化被消除，而在SLP-76缺陷型小鼠或Btk缺陷型X连锁无球蛋白血症（XLA）人血小板中，LAT酪氨酸磷酸化没有改变。使用工程改造为缺少衔接子LAT的小鼠，我们显示LAT缺陷型血小板中Syk和Btk的酪氨酸磷酸化响应CRP得以维持，而SLP-76的磷酸化受到轻微损害。相反，在缺乏LAT的血小板中PLCγ2的酪氨酸磷酸化显着降低，但没有被完全抑制。 PLCγ2磷酸化的减少与磷脂酸，1,2-二酰甘油的代谢产物，pleckstrin的磷酸化，蛋白激酶C的底物以及响应CRP的P-选择素的表达受到显着抑制有关。响应凝血酶，参数没有改变。在缺乏LAT的血小板中，纤维蛋白原受体整合素α IIb β 3 响应CRP的激活也减少了，但并未被完全抑制。这些结果表明，LAT酪氨酸磷酸化发生在Syk的下游，并且与衔接子SLP-76无关，并且它们在LAT在PLCγ2的磷酸化和活化中起主要作用，从而导致下游反应，例如α-颗粒分泌和活化。整联蛋白α IIb β 3 。结果进一步表明，SLP-76酪氨酸磷酸化的主要途径与LAT无关，并且PLCγ2的酪氨酸磷酸化有一个次要的，不依赖LAT的途径。我们提出了一个模型，其中LAT和SLP-76是PLCγ2磷酸化所必需的，但它们是通过Syk下游的独立途径调控的。

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