Coordinate interactions of Csk, Src, and Syk kinases with [alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton.
Coordinate interactions of Csk, Src, and Syk kinases with [alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton.
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DOI：
10.1083/jcb.200112113
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发表时间：
2002-04-15
期刊：
影响因子：
--
通讯作者：
Shattil SJ
中科院分区：
文献类型：
--
作者：
Obergfell A;Eto K;Mocsai A;Buensuceso C;Moores SL;Brugge JS;Lowell CA;Shattil SJ
整合素通过酪氨酸激酶调节细胞粘附和运动，但对该过程的启动知之甚少。我们发现Src与血小板中的整合素αIIbβ3组成性结合。血小板与纤维蛋白原的粘附导致αIIbβ3相关Src活性迅速增加，活性Src定位于丝状伪足和细胞边缘。Csk通过磷酸化Tyr-529负调节Src，也与αIIbβ3组成性相关。然而，纤维蛋白原结合导致Csk与αIIbβ3解离，同时伴有Src Tyr-529的去磷酸化和Src激活环Tyr-418的磷酸化。与Src和Csk的行为相反，Syk仅在纤维蛋白原结合后与αIIbβ3相关。Src、Hck、Fgr和林恩多重缺陷的血小板或经Src激酶抑制剂处理的正常血小板不能在纤维蛋白原上扩散。Src激酶的抑制阻断了Syk的活化，并抑制了参与细胞骨架调节的Syk底物（Vav 1，Vav 3，SLP-76）的磷酸化。Syk缺陷型血小板在与纤维蛋白原粘附时表现出Src活化，但Vav 1、Vav 3和SLP-76没有扩散或磷酸化。这些研究证实，血小板在纤维蛋白原上的铺展需要αIIbβ3附近Src和Syk的顺序激活，从而为启动整合素信号传导至肌动蛋白细胞骨架提供了范例。
Integrins regulate cell adhesion and motility through tyrosine kinases, but initiation of this process is poorly understood. We find here that Src associates constitutively with integrin αIIbβ3 in platelets. Platelet adhesion to fibrinogen caused a rapid increase in αIIbβ3-associated Src activity, and active Src localized to filopodia and cell edges. Csk, which negatively regulates Src by phosphorylating Tyr-529, was also constitutively associated with αIIbβ3. However, fibrinogen binding caused Csk to dissociate from αIIbβ3, concomitant with dephosphorylation of Src Tyr-529 and phosphorylation of Src activation loop Tyr-418. In contrast to the behavior of Src and Csk, Syk was associated with αIIbβ3 only after fibrinogen binding. Platelets multiply deficient in Src, Hck, Fgr, and Lyn, or normal platelets treated with Src kinase inhibitors failed to spread on fibrinogen. Inhibition of Src kinases blocked Syk activation and inhibited phosphorylation of Syk substrates (Vav1, Vav3, SLP-76) implicated in cytoskeletal regulation. Syk-deficient platelets exhibited Src activation upon adhesion to fibrinogen, but no spreading or phosphorylation of Vav1, Vav3, and SLP-76. These studies establish that platelet spreading on fibrinogen requires sequential activation of Src and Syk in proximity to αIIbβ3, thus providing a paradigm for initiation of integrin signaling to the actin cytoskeleton.
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影响因子：
4.8
作者：
Gallet, C;Rosa, JP;Maclouf, J
通讯作者：
Maclouf, J
DOI：
10.1006/bbrc.2001.5355
发表时间：
2001-08-10
影响因子：
3.1
作者：
Inatome, R;Yanagi, S;Yamamura, H
通讯作者：
Yamamura, H
DOI：
10.1073/pnas.83.4.852
发表时间：
1986-02-01
影响因子：
11.1
作者：
GOLDEN, A;NEMETH, SP;BRUGGE, JS
通讯作者：
BRUGGE, JS
影响因子：
11.4
作者：
HORVATH, AR;MUSZBEK, L;KELLIE, S
通讯作者：
KELLIE, S
影响因子：
4.8
作者：
Cheng, A;Bal, GS;Tremblay, ML
通讯作者：
Tremblay, ML