Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A1, Canada.
J Cell Biol. 2012 Dec 10;199(6):951-67. doi: 10.1083/jcb.201206051. Epub 2012 Dec 3.
The small GTPase Rap1 regulates inside-out integrin activation and thereby influences cell adhesion, migration, and polarity. Several Rap1 effectors have been described to mediate the cellular effects of Rap1 in a context-dependent manner. Radil is emerging as an important Rap effector implicated in cell spreading and migration, but the molecular mechanisms underlying its functions are unclear. We report here that the kinesin KIF14 associates with the PDZ domain of Radil and negatively regulates Rap1-mediated inside-out integrin activation by tethering Radil on microtubules. The depletion of KIF14 led to increased cell spreading, altered focal adhesion dynamics, and inhibition of cell migration and invasion. We also show that Radil is important for breast cancer cell proliferation and for metastasis in mice. Our findings provide evidence that the concurrent up-regulation of Rap1 activity and increased KIF14 levels in several cancers is needed to reach optimal levels of Rap1-Radil signaling, integrin activation, and cell-matrix adhesiveness required for tumor progression.
小分子 GTPase Rap1 调节细胞内整合素的激活，从而影响细胞黏附、迁移和极性。已有多种 Rap1 效应物被描述为以依赖于上下文的方式介导 Rap1 的细胞效应。Radil 作为一种重要的 Rap 效应物，参与细胞扩展和迁移，但它的功能的分子机制尚不清楚。我们在这里报告，驱动蛋白 KIF14 与 Radil 的 PDZ 结构域结合，并通过将 Radil 锚定在微管上来负调控 Rap1 介导的细胞内整合素激活。KIF14 的耗竭导致细胞扩展增加、焦点黏附动力学改变以及细胞迁移和侵袭抑制。我们还表明 Radil 对乳腺癌细胞增殖和小鼠转移很重要。我们的研究结果提供了证据，表明在几种癌症中，Rap1 活性的上调和 KIF14 水平的增加是必需的，以达到肿瘤进展所需的 Rap1-Radil 信号、整合素激活和细胞-基质黏附的最佳水平。
