PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE
PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE
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DOI：
10.1038/ncb1675
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发表时间：
2008-02-01
影响因子：
21.3
通讯作者：
Sahai, Erik
中科院分区：
文献类型：
--
作者：
Pinner, Sophie;Sahai, Erik
在三维基质中，癌细胞以圆形、变形虫状形态移动，其由肌动球蛋白的ROCK依赖性收缩控制。在这项研究中，我们表明，PDK 1是所需的肌球蛋白轻链和细胞运动的磷酸化，无论是在可变形凝胶和体内。PDK 1的消耗改变了ROCK 1的定位，并降低了其驱动皮质肌动蛋白-肌球蛋白收缩的能力。这种形式的ROCK 1调节不需要PDK 1激酶活性，而是涉及PDK 1与ROCK 1在质膜上的直接结合; PDK 1直接与RhoE竞争结合ROCK 1。在没有PDK 1的情况下，RhoE的负调节占主导地位，导致肌动蛋白-肌球蛋白收缩性和运动性降低。这项工作揭示了PDK 1在调节皮质肌动蛋白和细胞运动中的一种新的非催化作用。
In three-dimensional matrices cancer cells move with a rounded, amoeboid morphology that is controlled by ROCK-dependent contraction of acto-myosin. In this study, we show that PDK1 is required for phosphorylation of myosin light chain and cell motility, both on deformable gels and in vivo. Depletion of PDK1 alters the localization of ROCK1 and reduces its ability to drive cortical acto-myosin contraction. This form of ROCK1 regulation does not require PDK1 kinase activity, but instead involves direct binding of PDK1 to ROCK1 at the plasma membrane; PDK1 competes directly with RhoE for binding to ROCK1. In the absence of PDK1, negative regulation by RhoE predominates, causing reduced acto-myosin contractility and motility. This work uncovers a novel non-catalytic role for PDK1 in regulating cortical acto-myosin and cell motility.