Signaling Scaffold Protein IQGAP1 Interacts with Microtubule Plus-end Tracking Protein SKAP and Links Dynamic Microtubule Plus-end to Steer Cell Migration
Signaling Scaffold Protein IQGAP1 Interacts with Microtubule Plus-end Tracking Protein SKAP and Links Dynamic Microtubule Plus-end to Steer Cell Migration
复制标题
信号支架蛋白 IQGAP1 与微管正端追踪蛋白 SKAP 相互作用，并连接动态微管正端以引导细胞迁移
DOI：
10.1074/jbc.m115.673517
复制
发表时间：
2015-09-25
影响因子：
4.8
通讯作者：
Yao, Xuebiao
中科院分区：
文献类型：
--
作者：
Cao, Dan;Su, Zeqi;Yao, Xuebiao
细胞迁移是由微管与质膜皮层的动态相互作用协调的。然而，皮质肌动蛋白细胞骨架和微管动力学的调控机制的特点较少。我们早期的研究表明，小GTP酶激活蛋白IQGAP调节上皮细胞的极化分泌（1）。在这里，我们表明IQGAP 1通过与正末端跟踪蛋白SKAP相互作用来连接动态微管以引导细胞迁移。生物化学表征显示IQGAP 1和SKAP形成同源复合物，并且它们的结合界面分别映射到SKAP的WWIQ基序和C-末端。WWIQ肽在体外破坏IQGAP 1和SKAP之间的生物化学相互作用，并且使用膜可渗透的TAT-WWIQ肽在体内干扰IQGAP 1-SKAP相互作用导致抑制EGF引起的定向细胞迁移。在迁移细胞中，SKAP的N-末端与EB 1结合，其C末端与IQGAP 1结合。因此，我们的理由是，一种新的IQGAP 1复合物通过将动态微管加端耦合到细胞皮层来协调定向细胞迁移。
Cell migration is orchestrated by dynamic interaction of microtubules with the plasma membrane cortex. However, the regulatory mechanisms underlying the cortical actin cytoskeleton and microtubule dynamics are less characterized. Our earlier study showed that small GTPase-activating proteins, IQGAPs, regulate polarized secretion in epithelial cells (1). Here, we show that IQGAP1 links dynamic microtubules to steer cell migration via interacting with the plus-end tracking protein, SKAP. Biochemical characterizations revealed that IQGAP1 and SKAP form a cognate complex and that their binding interfaces map to the WWIQ motif and the C-terminal of SKAP, respectively. The WWIQ peptide disrupts the biochemical interaction between IQGAP1 and SKAP in vitro, and perturbation of the IQGAP1-SKAP interaction in vivo using a membrane-permeable TAT-WWIQ peptide results in inhibition of directional cell migration elicited by EGF. Mechanistically, the N-terminal of SKAP binds to EB1, and its C terminus binds to IQGAP1 in migrating cells. Thus, we reason that a novel IQGAP1 complex orchestrates directional cell migration via coupling dynamic microtubule plus-ends to the cell cortex.