The Cdk inhibitor p57Kip2 controls LIM-kinase 1 activity and regulates actin cytoskeleton dynamics
The Cdk inhibitor p57Kip2 controls LIM-kinase 1 activity and regulates actin cytoskeleton dynamics
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DOI：
10.1038/onc.2009.269
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发表时间：
2009-11-26
期刊：
影响因子：
8
通讯作者：
Joseph, B.
中科院分区：
文献类型：
--
作者：
Vlachos, P.;Joseph, B.
细胞周期蛋白依赖性激酶抑制因子p57(Kip2)基因被认为是一种肿瘤抑制基因，在多种癌症类型中被失活，与肿瘤进展和患者预后不良有关。在这里，我们报告p57(Kip2)与肌动蛋白细胞骨架修饰酶LIM-KK-1(LIMK-1)相互作用，但不与LIMK-2相互作用。这种相互作用增强了LIMK-1的活性，而不依赖于其激活剂Rho相关的激酶。这导致了肌动蛋白解聚因子Cofilin的磷酸化增加和随后的失活。相应地，选择性p57(Kip2)的表达促进癌细胞中肌动蛋白应激纤维的形成。对荧光标记的肌动蛋白进行光漂白后的荧光恢复分析进一步证明，p57(Kip2)的表达导致肌动蛋白可移动部分减少，从而影响其在细胞内的周转率。最后，我们提出证据表明，LIMK-1的p57(Kip2)控制最终对细胞迁移率产生负面影响。因此，这些结果表明，除了p57(Kip2)在控制细胞增殖和死亡方面的既定功能外，p57(Kip2)在调节肌动蛋白细胞骨架动态以及通过这一途径调节癌细胞的迁移能力方面也是至关重要的。Oncogene(2009年)28,41754188；doi：10.1038/onc.2009.269；2009年9月7日在线发布
The cyclin-dependent kinase inhibitor p57(Kip2) gene has been suggested to be a tumor suppressor gene, being inactivated in various cancer types, linked to tumor progression and poor patient outcome. Here, we report that p57(Kip2) interacts with the actin cytoskeleton modifying enzyme, LIM-kinase 1 (LIMK-1) but not LIMK-2. This interaction enhances activity of LIMK-1, independently of its activator Rho-associated kinase. This resulted in an increased phosphorylation and consequent inactivation of the actin depolymerization factor, cofilin. In accordance, selective p57(Kip2) expression promotes actin stress fiber formation in cancer cells. Fluorescence recovery after photobleaching analysis of fluorescent-labeled actin further demonstrated that p57(Kip2) expression results in reduction of actin protein mobile fraction, which affects its turnover rate in cell. Finally, we present evidence that the p57(Kip2) control of LIMK-1 ultimately affects cell mobility negatively. Thus, in addition to its established function in control of proliferation and cell death, these results indicate that p57(Kip2) is critical in the regulation of actin cytoskeleton dynamic and by this means migration ability of cancer cells. Oncogene (2009) 28, 4175-4188; doi: 10.1038/onc.2009.269; published online 7 September 2009