LKB1肿瘤抑制蛋白通过Rho及其交换因子Dbl独立于激酶活性来调节肌动蛋白丝组装。
LKB1 tumor suppressor protein regulates actin filament assembly through Rho and its exchange factor Dbl independently of kinase activity.
作者信息
Xu Xiaojian, Omelchenko Tatiana, Hall Alan
机构信息
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
出版信息
BMC Cell Biol. 2010 Oct 12;11:77. doi: 10.1186/1471-2121-11-77.
BACKGROUND
Germline mutations in LKB1 result in Peutz-Jeghers Syndrome characterized by intestinal hamartomas and increased incidence of epithelial cancers. LKB1 encodes a serine/threonine kinase that plays an important role in regulating energy metabolism through the AMPK/mTOR signaling pathway. In addition, LKB1 is homologous to PAR-4, a polarity protein first described in C. elegans, while activation of LKB1 in mammalian epithelial cells induces the polarized assembly of actin filaments.
RESULTS
To explore the mechanism by which LKB1 interacts with the actin cytoskeleton, we introduced LKB1 into HeLa cells that lack endogenous LKB1. This results in activation of the small GTPase Rho and the assembly of linear actin filaments associated with focal adhesions. These effects on the actin cytoskeleton are attenuated by siRNA-mediated depletion of the guanine nucleotide exchange factor Dbl. Co-expression of the LKB1 with the adaptor protein STRAD induces actin filament puncta associated with phospho-ezrin.
CONCLUSIONS
This study reveals that LKB1 regulates the actin cytoskeleton through a Dbl/Rho pathway.
背景
LKB1基因的种系突变导致黑斑息肉综合征，其特征为肠道错构瘤和上皮癌发病率增加。LKB1编码一种丝氨酸/苏氨酸激酶，该激酶通过AMPK/mTOR信号通路在调节能量代谢中发挥重要作用。此外，LKB1与PAR-4同源，PAR-4是一种最早在秀丽隐杆线虫中描述的极性蛋白，而在哺乳动物上皮细胞中LKB1的激活会诱导肌动蛋白丝的极化组装。
结果
为了探究LKB1与肌动蛋白细胞骨架相互作用的机制，我们将LKB1导入缺乏内源性LKB1的HeLa细胞中。这导致小GTP酶Rho的激活以及与粘着斑相关的线性肌动蛋白丝的组装。siRNA介导的鸟嘌呤核苷酸交换因子Dbl的缺失减弱了这些对肌动蛋白细胞骨架的影响。LKB1与衔接蛋白STRAD的共表达诱导了与磷酸化埃兹蛋白相关的肌动蛋白丝斑点。
结论
本研究揭示LKB1通过Dbl/Rho途径调节肌动蛋白细胞骨架。
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