IQGAP1 and calmodulin modulate E-cadherin function
IQGAP1 and calmodulin modulate E-cadherin function
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DOI：
10.1074/jbc.274.53.37885
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发表时间：
1999-12-31
影响因子：
4.8
通讯作者：
Sacks, DB
中科院分区：
文献类型：
--
作者：
Li, ZG;Kim, SH;Sacks, DB
钙依赖性细胞间粘附是由钙粘蛋白家族的跨膜蛋白介导的。粘附是通过相邻细胞上的钙粘蛋白的胞外结构域的嗜同性相互作用实现的，其中胞质区域用于将复合物偶联到细胞骨架。IQGAP 1是一种新的RasGAP相关蛋白，与细胞骨架相互作用，与肌动蛋白、Rho家族成员和E-钙粘蛋白结合，钙调蛋白与IQGAP 1结合并调节其与Cdc 42和肌动蛋白的结合。在这里，我们证明了钙调蛋白和E-钙粘蛋白之间的竞争，结合IQGAP 1在体外和正常的细胞环境。MCF-7（E-钙粘蛋白阳性）和MDA-MB-231（E-钙粘蛋白阴性）上皮细胞的免疫细胞化学分析显示，E-钙粘蛋白是IQGAP 1在细胞-细胞连接处积累所必需的。细胞渗透性钙调蛋白拮抗剂CGS 9343 B显著增加MCF-7细胞-细胞接触区域的IQGAP 1，同时细胞-细胞连接处的E-钙粘蛋白量减少。E-钙粘蛋白功能分析显示，CGS 9343 B显着降低了嗜同性E-钙粘蛋白粘附。在这些数据的基础上，我们提出，钙调蛋白与IQGAP 1结合的破坏增强了IQGAP 1与细胞间钙粘蛋白-连环蛋白复合物组分的结合。细胞连接，导致E-钙粘蛋白功能受损。
Ca2+-dependent cell-cell adhesion is mediated by the cadherin family of transmembrane proteins. Adhesion is achieved by homophilic interaction of the extracellular domains of cadherins on adjacent cells, with the cytoplasmic regions serving to couple the complex to the cytoskeleton. IQGAP1, a novel RasGAP-related protein that interacts with the cytoskeleton, binds to actin, members of the Rho family, and E-cadherin, Calmodulin binds to IQGAP1 and regulates its association with Cdc42 and actin. Here we demonstrate competition between calmodulin and E-cadherin for binding to IQGAP1 both in vitro and in a normal cellular milieu. Immunocytochemical analysis in MCF-7 (E-cadherin positive) and MDA-MB-231 (E-cadherin negative) epithelial cells revealed that E-cadherin is required for accumulation of IQGAP1 at cell-cell junctions. The cell-permeable calmodulin antagonist CGS9343B significantly increased IQGAP1 at areas of MCF-7 cell-cell contact, with a concomitant decrease in the amount of E-cadherin at cell-cell junctions. Analysis of E-cadherin function revealed that CGS9343B significantly decreased homophilic E-cadherin adhesion, On the basis of these data, we propose that disruption of the binding of calmodulin to IQGAP1 enhances the association of IQGAP1 with components of the cadherin-catenin complex at cell-cell junctions, resulting in impaired E-cadherin function.