A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function.
A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function.
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DOI：
10.1084/jem.20100222
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发表时间：
2010-08-30
期刊：
影响因子：
--
通讯作者：
Hartwig JH
中科院分区：
文献类型：
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作者：
Falet H;Pollitt AY;Begonja AJ;Weber SE;Duerschmied D;Wagner DD;Watson SP;Hartwig JH
丝蛋白A （FlnA）交联肌动蛋白丝，并将血管性血友病因子受体GPIb-IX-V连接到血小板中潜在的细胞骨架上。由于FlnA缺乏是胚胎致死性的，因此通过将FlnAloxP/loxP雌性与GATA1-Cre雄性杂交产生血小板中缺乏FlnA的小鼠。FlnAloxP/y GATA1-Cre雄性有大量血小板减少症和尾出血次数增加。flna缺失的血小板表达减少，GPIbα表面分布改变，因为它们缺乏GPIbα与肌动蛋白丝的正常细胞骨架连接。这导致在剪切速率为1500 /s时，与野生型血小板相比，胶原包被表面的血小板覆盖率减少约70%。然而，出乎意料的是，免疫受体酪氨酸激活基元(ITAM)-和ITAM样介导的信号在FlnA-null血小板中严重受损。flna缺失的血小板在受到胶原受体GPVI和C型凝集素样受体2的刺激后，无法扩散，α-颗粒分泌减少，整合素α ib β3活化减少，蛋白酪氨酸磷酸化减少，尤其是蛋白酪氨酸激酶Syk和磷脂酶C -γ2的磷酸化减少。这种信号缺陷可以追溯到新的FlnA - Syk相互作用的缺失，因为Syk在免疫球蛋白样重复5上与FlnA结合。我们的研究结果表明，FlnA和Syk之间的相互作用调节ITAM-和含有ITAM样的受体信号传导和血小板功能。
Filamin A (FlnA) cross-links actin filaments and connects the Von Willebrand factor receptor GPIb-IX-V to the underlying cytoskeleton in platelets. Because FlnA deficiency is embryonic lethal, mice lacking FlnA in platelets were generated by breeding FlnAloxP/loxP females with GATA1-Cre males. FlnAloxP/y GATA1-Cre males have a macrothrombocytopenia and increased tail bleeding times. FlnA-null platelets have decreased expression and altered surface distribution of GPIbα because they lack the normal cytoskeletal linkage of GPIbα to underlying actin filaments. This results in ∼70% less platelet coverage on collagen-coated surfaces at shear rates of 1,500/s, compared with wild-type platelets. Unexpectedly, however, immunoreceptor tyrosine-based activation motif (ITAM)- and ITAM-like–mediated signals are severely compromised in FlnA-null platelets. FlnA-null platelets fail to spread and have decreased α-granule secretion, integrin αIIbβ3 activation, and protein tyrosine phosphorylation, particularly that of the protein tyrosine kinase Syk and phospholipase C–γ2, in response to stimulation through the collagen receptor GPVI and the C-type lectin-like receptor 2. This signaling defect was traced to the loss of a novel FlnA–Syk interaction, as Syk binds to FlnA at immunoglobulin-like repeat 5. Our findings reveal that the interaction between FlnA and Syk regulates ITAM- and ITAM-like–containing receptor signaling and platelet function.