PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR gamma to induce slow leukocyte rolling.
PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR gamma to induce slow leukocyte rolling.
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DOI：
10.1084/jem.20072660
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发表时间：
2008-09-29
期刊：
影响因子：
--
通讯作者：
Ley K
中科院分区：
文献类型：
--
作者：
Zarbock A;Abram CL;Hundt M;Altman A;Lowell CA;Ley K
E-选择素与P-选择素糖蛋白配体-1(P-选择素糖蛋白配体-1)结合可通过脾酪氨酸激酶(Syk)信号通路激活β-2整合素淋巴细胞功能相关抗原-1。这种信号不依赖于GαI蛋白偶联受体，导致缓慢滚动，并促进中性粒细胞重新聚集到炎症部位。然而，将PSGL-1的E-选择素参与与Syk激活联系起来的信号通路尚不清楚。为了测试Src家族蛋白和含有免疫受体酪氨酸激活基序(ITAM)的接头蛋白的作用，我们在流室、活体显微镜和腹膜炎研究中使用了不同的基因缺陷小鼠。FGR−/−或Hck−/−LYN−/−FGR−/−小鼠中性粒细胞中E-选择素介导的Syk和Slow Rolling的磷酸化被取消。来自Tyrobp−/−Fcrg−/−小鼠的中性粒细胞缺乏DAP12和FcRγ，不能维持中性粒细胞对E-选择素和细胞间黏附分子-1的缓慢滚动，也不能磷酸化Syk和p38MAPK。这一缺陷通过使用混合嵌合小鼠在体内得到证实。在Tyrobpα−/−Fcrg−/−小鼠中，G Fcrg I非依赖性中性粒细胞募集到炎症的腹膜腔显著受到抑制。我们的数据表明，一条依赖于ITAM的途径，涉及Src家族的激酶FGR和含有ITAM的适配蛋白DAP12和FCRγ，参与了PSGL-1下游的初始信号事件，这是启动中性粒细胞缓慢滚动所必需的。
E-selectin binding to P-selectin glycoprotein ligand-1 (PSGL-1) can activate the β2 integrin lymphocyte function-associated antigen-1 by signaling through spleen tyrosine kinase (Syk). This signaling is independent of Gαi-protein–coupled receptors, results in slow rolling, and promotes neutrophil recruitment to sites of inflammation. However, the signaling pathways linking E-selectin engagement of PSGL-1 to Syk activation are unknown. To test the role of Src family kinases and immunoreceptor tyrosine-based activating motif (ITAM)–containing adaptor proteins, we used different gene-deficient mice in flow chamber, intravital microscopy, and peritonitis studies. E-selectin–mediated phosphorylation of Syk and slow rolling was abolished in neutrophils from fgr−/− or hck−/− lyn−/− fgr−/− mice. Neutrophils from Tyrobp−/− Fcrg−/− mice lacking both DAP12 and FcRγ were incapable of sustaining slow neutrophil rolling on E-selectin and intercellular adhesion molecule-1 and were unable to phosphorylate Syk and p38 MAPK. This defect was confirmed in vivo by using mixed chimeric mice. Gαi-independent neutrophil recruitment into the inflamed peritoneal cavity was sharply suppressed in Tyrobp−/− Fcrg−/− mice. Our data demonstrate that an ITAM-dependent pathway involving the Src-family kinase Fgr and the ITAM-containing adaptor proteins DAP12 and FcRγ is involved in the initial signaling events downstream of PSGL-1 that are required to initiate neutrophil slow rolling.
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影响因子：
32.4
作者：
Bakker, ABH;Hoek, RM;Lanier, LL
通讯作者：
Lanier, LL
影响因子：
20.3
作者：
Dunne, JL;Ballantyne, CM;Ley, K
通讯作者：
Ley, K
DOI：
10.1083/jcb.133.4.895
发表时间：
1996-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lowell CA;Fumagalli L;Berton G
通讯作者：
Berton G
DOI：
10.1073/pnas.88.16.7410
发表时间：
1991-08-01
影响因子：
11.1
作者：
BURKHARDT, AL;BRUNSWICK, M;MOND, JJ
通讯作者：
MOND, JJ
影响因子：
20.3
作者：
Abbal, Claire;Lambelet, Martine;Spertini, Olivier
通讯作者：
Spertini, Olivier