JAM-A regulates cortical dynein localization through Cdc42 to control planar spindle orientation during mitosis.
JAM-A regulates cortical dynein localization through Cdc42 to control planar spindle orientation during mitosis.
复制标题
DOI：
10.1038/ncomms9128
复制
发表时间：
2015-08-26
影响因子：
16.6
通讯作者：
Ebnet K
中科院分区：
文献类型：
--
作者：
Tuncay H;Brinkmann BF;Steinbacher T;Schürmann A;Gerke V;Iden S;Ebnet K
极化上皮细胞中纺锤体的平面取向取决于动力蛋白-动力蛋白马达蛋白复合体在外侧皮质的准确定位。细胞黏附分子对动力蛋白-动力蛋白复合体的皮质定位的作用还知之甚少。在这里，我们发现连接黏附分子-A(JAM-A)在上皮形态发生过程中调节有丝分裂纺锤体的平面方向。在有丝分裂过程中，JAM-A触发CDC42和PI(3)K的瞬时激活，在皮质产生PtdIns(3，4，5)P3的梯度，并调节皮质肌动蛋白细胞骨架的形成。在缺乏功能性JAM-A的情况下，动力蛋白在皮质的定位减少，有丝分裂纺锤体错位，三维培养中的上皮形态发生受到影响。我们的发现表明，依赖PI(3)K和皮质F-肌动蛋白的平面纺锤体定向通路在极化的上皮细胞中起调节上皮形态发生的作用，我们认为JAM-A是这一通路的连接调节因子。极化的上皮细胞将它们的有丝分裂纺锤体定向在薄片平面上，但细胞黏附分子在这一过程中的作用尚不清楚。在这里，Tuncay等人。研究表明，JAM-A通过产生PtdIns(3，4，5)P3的梯度，调节皮质肌动蛋白组装，并将dynactin定位于细胞皮质，来调节纺锤体的方向。
Planar spindle orientation in polarized epithelial cells depends on the precise localization of the dynein–dynactin motor protein complex at the lateral cortex. The contribution of cell adhesion molecules to the cortical localization of the dynein–dynactin complex is poorly understood. Here we find that junctional adhesion molecule-A (JAM-A) regulates the planar orientation of the mitotic spindle during epithelial morphogenesis. During mitosis, JAM-A triggers a transient activation of Cdc42 and PI(3)K, generates a gradient of PtdIns(3,4,5)P3 at the cortex and regulates the formation of the cortical actin cytoskeleton. In the absence of functional JAM-A, dynactin localization at the cortex is reduced, the mitotic spindle apparatus is misaligned and epithelial morphogenesis in three-dimensional culture is compromised. Our findings indicate that a PI(3)K- and cortical F-actin-dependent pathway of planar spindle orientation operates in polarized epithelial cells to regulate epithelial morphogenesis, and we identify JAM-A as a junctional regulator of this pathway. Polarized epithelial cells orient their mitotic spindles in the plane of the sheet but the role of cell adhesion molecules in this process is poorly understood. Here Tuncay et al. show that JAM-A regulates spindle orientation by creating a gradient of PtdIns(3,4,5)P3, regulating cortical actin assembly and localizing dynactin to the cell cortex.