Beatson Institute for Cancer Research, G61 1BD Glasgow, Scotland, UK.
J Cell Biol. 2012 Jan 23;196(2):277-95. doi: 10.1083/jcb.201109112.
Inhibition of αvβ3 integrin or expression of oncogenic mutants of p53 promote invasive cell migration by enhancing endosomal recycling of α5β1 integrin under control of the Rab11 effector Rab-coupling protein (RCP). In this paper, we show that diacylglycerol kinase α (DGK-α), which phosphorylates diacylglycerol to phosphatidic acid (PA), was required for RCP to be mobilized to and tethered at the tips of invasive pseudopods and to allow RCP-dependent α5β1 recycling and the resulting invasiveness of tumor cells. Expression of a constitutive-active mutant of DGK-α drove RCP-dependent invasion in the absence of mutant p53 expression or αvβ3 inhibition, and conversely, an RCP mutant lacking the PA-binding C2 domain was not capable of being tethered at pseudopod tips. These data demonstrate that generation of PA downstream of DGK-α is essential to connect expression of mutant p53s or inhibition of αvβ3 to RCP and for this Rab11 effector to drive the trafficking of α5β1 that is required for tumor cell invasion through three-dimensional matrices.
αvβ3 整合素的抑制或 p53 致癌突变体的表达通过增强 Rab11 效应因子 Rab 连接蛋白 (RCP) 控制下的 α5β1 整合素的内体再循环促进侵袭性细胞迁移。在本文中，我们表明，二酰基甘油激酶 α (DGK-α) 将二酰基甘油磷酸化为磷脂酸 (PA)，这对于 RCP 被募集到侵袭性伪足的尖端并被束缚在那里以及允许 RCP 依赖性的 α5β1 再循环和由此产生的肿瘤细胞侵袭性是必需的。DGK-α 的组成性活性突变体的表达在没有突变型 p53 表达或 αvβ3 抑制的情况下驱动 RCP 依赖性侵袭，相反，缺乏 PA 结合 C2 结构域的 RCP 突变体不能被束缚在伪足尖端。这些数据表明，DGK-α 下游 PA 的产生对于将突变型 p53 的表达或 αvβ3 的抑制与 RCP 连接起来，以及对于这种 Rab11 效应因子驱动α5β1 的运输是必需的，α5β1 的运输是肿瘤细胞通过三维基质侵袭所必需的。
