The Abl/Arg substrate ArgBP2/nArgBP2 coordinates the function of multiple regulatory mechanisms converging on the actin cytoskeleton
The Abl/Arg substrate ArgBP2/nArgBP2 coordinates the function of multiple regulatory mechanisms converging on the actin cytoskeleton
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DOI：
10.1073/pnas.0409376102
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发表时间：
2005-02-01
影响因子：
11.1
通讯作者：
De Camilli, P
中科院分区：
文献类型：
--
作者：
Cestra, G;Toomre, D;De Camilli, P
ArgBP 2及其脑特异性剪接变体nArgBP 2是Abl/Arg酪氨酸激酶和泛素连接酶Cbl的相互作用物和底物。它们是衔接蛋白家族的成员，与肌动蛋白共定位于应力纤维和细胞粘附位点，包括神经元突触。在这里，我们表明，他们的NH 2-末端区域，其中包含一个sorbin同源结构域域，相互作用与血影蛋白，我们确定其COOH-末端SH 3结构域的结合蛋白。所有这些结合伴侣都参与肌动蛋白细胞骨架的调节。这些包括发动蛋白，synaptojanin和WAVE亚型，以及WAVE调节蛋白。至少有两个ArgBP 2/nArgBP 2结合伙伴，synaptojanin 213和WAVE 2，经历泛素化和酪氨酸磷酸化。ArgBP 2/nArgBP 2在星形胶质细胞敲低产生的粘着斑蛋白的重新分布和周边肌动蛋白皱褶的增加，而nArgBP 2过表达产生的肌动蛋白细胞骨架的崩溃。因此，ArgBP 2/nArgBP 2是一种支架蛋白，通过协调会聚在肌动蛋白细胞骨架上的多种信号通路的功能来控制粘附和运动之间的平衡。
ArgBP2, and its brain-specific splice variant, nArgBP2, are interactors and substrates of Abl/Arg tyrosine kinases and of the ubiquitin ligase Cbl. They are members of a family of adaptor proteins that colocalize with actin on stress fibers and at cell-adhesion sites, including neuronal synapses. We show here that their NH2-terminal region, which contains a sorbin homology domain domain, interacts with spectrin, and we identify binding proteins for their COOH-terminal SH3 domains. All these binding partners participate in the regulation of the actin cytoskeleton. These include dynamin, synaptojanin, and WAVE isoforms, as well as WAVE regulatory proteins. At least two of the ArgBP2/nArgBP2 binding partners, synaptojanin 213 and WAVE2, undergo ubiquitination and Abl-dependent tyrosine phosphorylation. ArgBP2/nArgBP2 knockdown in astrocytes produces a redistribution of focal adhesion proteins and an increase in peripheral actin ruffles, whereas nArgBP2 overexpression produces a collapse of the actin cytoskeleton. Thus, ArgBP2/nArgBP2 is a scaffold protein that control the balance between adhesion and motility by coordinating the function of multiple signaling pathways converging on the actin cytoskeleton.