LIMD1 phosphorylation in mitosis is required for mitotic progression and its tumor-suppressing activity
LIMD1 phosphorylation in mitosis is required for mitotic progression and its tumor-suppressing activity
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有丝分裂中的 LIMD1 磷酸化是有丝分裂进展及其肿瘤抑制活性所必需的
DOI：
10.1111/febs.14743
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发表时间：
2019-03-01
期刊：
影响因子：
5.4
通讯作者：
Dong, Jixin
中科院分区：
文献类型：
--
作者：
Zhou, Jiuli;Zhang, Lin;Dong, Jixin
LIM domain containing 1（LIMD 1）是Zyxin家族蛋白质的成员，并且在肺癌中作为肿瘤抑制剂起作用。LIMD 1已被证明可以调节Hippo-YAP信号传导活性。在这里，我们报告了LIMD 1的一种新的调节机制。我们发现细胞周期蛋白依赖性激酶1（CDK 1）和c-Jun NH 2-末端激酶1/2（JNK 1/2）在体外和抗微管蛋白药物诱导的有丝分裂停滞期间在细胞中磷酸化LIMD 1。磷酸化也发生在正常有丝分裂期间。S272、S277、S421和S424被鉴定为LIMD 1的主要磷酸化位点。LIMD 1的缺失导致有丝分裂细胞周期缩短，并且LIMD 1的磷酸化是适当的有丝分裂进程所必需的。我们进一步表明，磷酸化缺陷突变LIMD 1 -4A在抑制肺癌细胞的细胞增殖、非贴壁依赖性生长、细胞迁移和侵袭方面活性较低。总之，我们的研究结果表明，LIMD 1是有丝分裂进程的关键调节因子，LIMD 1的失调有助于肿瘤发生。
LIM domains containing 1 (LIMD1) is a member of the Zyxin family proteins and functions as a tumor suppressor in lung cancer. LIMD1 has been shown to regulate Hippo-YAP signaling activity. Here, we report a novel regulatory mechanism for LIMD1. We found that cyclin-dependent kinase 1 (CDK1) and c-Jun NH2-terminal kinases 1/2 (JNK1/2) phosphorylate LIMD1 in vitro and in cells during anti-tubulin drug-induced mitotic arrest. Phosphorylation also occurs during normal mitosis. S272, S277, S421, and S424 were identified as the main phosphorylation sites in LIMD1. Deletion of LIMD1 resulted in a shortened mitotic cell cycle and phosphorylation of LIMD1 is required for proper mitotic progression. We further showed that the phosphorylation-deficient mutant LIMD1-4A is less active in suppressing cell proliferation, anchorage-independent growth, cell migration, and invasion in lung cancer cells. Together, our findings suggest that LIMD1 is a key regulator of mitotic progression, and that dysregulation of LIMD1 contributes to tumorigenesis.