Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells
Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells
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DOI：
10.1038/sj.onc.1210264
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发表时间：
2007-07-12
期刊：
影响因子：
8
通讯作者：
Clevenger, C. V.
中科院分区：
文献类型：
--
作者：
Miller, S. L.;Antico, G.;Clevenger, C. V.
催乳素（PRL）刺激乳腺癌细胞的细胞骨架重组和运动。在PRL受体信号传导过程中，Vav 2被磷酸化并被激活，这是一个由丝氨酸/苏氨酸激酶Nek 3调节的事件。考虑到Vav 2的调节作用，检查了Nek 3在PRL介导的运动和侵袭中的功能。Nek 3在中国仓鼠卵巢转染子中的过表达增强了细胞骨架重组对PRL的反应。相反，通过小干扰RNA（siRNA）下调Nek 3的表达减弱了PRL介导的细胞骨架重组、GT3 Rac 1的激活、T47 D细胞的细胞迁移和侵袭。此外，PRL刺激诱导Nek 3和桩蛋白之间的相互作用，并显着增加桩蛋白丝氨酸磷酸化，而Nek 3 siRNA转染的细胞表现出显着减少桩蛋白磷酸化。乳腺组织微阵列的分析也表明，与正常标本相比，恶性肿瘤中Nek 3表达显著上调。这些数据表明，Nek 3有助于PRL介导的乳腺癌运动性通过涉及Rac 1激活和桩蛋白磷酸化的机制。
Prolactin (PRL) stimulates the cytoskeletal re-organization and motility of breast cancer cells. During PRL receptor signaling, Vav2 becomes phosphorylated and activated, an event regulated by the serine/ threonine kinase Nek3. Given the regulatory role of Vav2, the function of Nek3 in PRL-mediated motility and invasion was examined. Overexpression of Nek3 in Chinese hamster ovary transfectants potentiated cytoskeletal re-organization in response to PRL. In contrast, downregulation of Nek3 expression by small-interfering RNA (siRNA) attenuated PRL-mediated cytoskeletal reorganization, activation of GTPase Rac1, cell migration and invasion of T47D cells. In addition, PRL stimulation induced an interaction between Nek3 and paxillin and significantly increased paxillin serine phosphorylation, whereas Nek3 siRNA-transfected cells showed a marked reduction in paxillin phosphorylation. Analysis of breast tissue microarrays also demonstrated a significant up-regulation of Nek3 expression in malignant versus normal specimens. These data suggest that Nek3 contributes to PRL-mediated breast cancer motility through mechanisms involving Rac1 activation and paxillin phosphorylation.