IQGAP1 stimulates actin assembly through the N-WASP-Arp2/3 pathway
IQGAP1 stimulates actin assembly through the N-WASP-Arp2/3 pathway
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DOI：
10.1074/jbc.m607711200
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发表时间：
2007-01-05
影响因子：
4.8
通讯作者：
Kroschewski, Ruth
中科院分区：
文献类型：
--
作者：
Le Clainche, Christophe;Schlaepfer, Dominik;Kroschewski, Ruth
IQGAP1是一种在癌症中过度表达的保守模块化蛋白质，参与在诸如黏附、迁移和胞质分裂等运动过程中肌动蛋白和微管的组织。多种蛋白质已被证明可与IQGAP1相互作用，包括小G蛋白Rac1和Cdc42、肌动蛋白、钙调蛋白、β -连环蛋白、微管正端结合蛋白CLIP170（细胞质连接蛋白）和腺瘤性息肉病 coli蛋白。然而，IQGAP1在细胞运动中控制肌动蛋白动力学的分子机制尚不清楚。定量共定位分析和IQGAP1的下调显示，IQGAP1控制片状伪足中N - WASP与Arp2/3复合物的共定位。免疫共沉淀支持IQGAP1和N - WASP之间在体内存在联系。下拉实验以及N - WASP和Arp2/3复合物的分支肌动蛋白聚合动力学测定表明，IQGAP1的C末端一半以类似于Cdc42的方式通过与其BR - CRIB结构域相互作用来激活N - WASP，而IQGAP1的N末端一半通过与IQGAP1的C末端区域结合来拮抗这种激活。我们提出，信号诱导的IQGAP1自身抑制折叠的解除使得N - WASP被激活，从而刺激Arp2/3依赖的肌动蛋白组装。
IQGAP1 is a conserved modular protein overexpressed in cancer and involved in organizing actin and microtubules in motile processes such as adhesion, migration, and cytokinesis. A variety of proteins have been shown to interact with IQGAP1, including the small G proteins Rac1 and Cdc42, actin, calmodulin, beta-catenin, the microtubule plus end-binding proteins CLIP170 (cytoplasmic linker protein) and adenomatous polyposis coli. However, the molecular mechanism by which IQGAP 1 controls actin dynamics in cell motility is not understood. Quantitative co-localization analysis and down-regulation of IQGAP1 revealed that IQGAP1 controls the co-localization of N-WASP with the Arp2/3 complex in lamellipodia. Co-immunoprecipitation supports an in vivo link between IQGAP1 and N-WASP. Pull-down experiments and kinetic assays of branched actin polymerization with N-WASP and Arp2/3 complex demonstrated that the C-terminal half of IQGAP1 activates N-WASP by interacting with its BR-CRIB domain in a Cdc42-like manner, whereas the N-terminal half of IQGAP1 antagonizes this activation by association with a C-terminal region of IQGAP1. We propose that signal-induced relief of the autoinhibited fold of IQGAP1 allows activation of N-WASP to stimulate Arp2/3-dependent actin assembly.