LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap.
LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap.
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DOI：
10.1038/onc.2012.431
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发表时间：
2013-08-29
期刊：
影响因子：
8
通讯作者：
Quilliam, L. A.
中科院分区：
文献类型：
--
作者：
Nguyen, H. B.;Babcock, J. T.;Wells, C. D.;Quilliam, L. A.
肝激酶B1（LKB 1）肿瘤抑制因子通过调节细胞代谢和顶基极性来抑制细胞生长。LKB 1限制细胞生长的最佳机制是通过激活AMP激活蛋白激酶/雷帕霉素靶点（AMPK/mTOR）途径来控制代谢。由于LKB 1也是极化上皮细胞抵抗增生所必需的，因此预计它通过其他机制发挥作用。最近，是相关蛋白（雅普）已出现作为一个转录辅激活因子，调节组织稳态响应细胞-细胞接触。因此，本研究探讨了雅普和LKB 1之间的可能联系。在缺少这种肿瘤抑制因子的HeLa细胞中恢复LKB 1表达，或在NTERT永生化角质形成细胞中shRNA敲低LKB 1，证明LKB 1促进雅普磷酸化、核排斥和蛋白酶体降解。磷酸化缺陷型雅普突变体拯救LKB 1表型的能力，如细胞增殖和细胞大小的降低，表明雅普抑制有助于LKB 1肿瘤抑制功能。然而，Lats 1/2敲低抑制LKB 1介导的雅普调节的失败表明LKB 1通过非经典途径向雅普信号传导。此外，LKB 1抑制雅普独立于AMPK或mTOR激活。这些发现揭示了LKB 1可能通过抑制雅普来限制癌细胞生长的新机制。
The liver kinase B1 (LKB1) tumor suppressor inhibits cell growth through its regulation of cellular metabolism and apical-basal polarity. The best understood mechanism whereby LKB1 limits cell growth is through activation of the AMP-activated-protein-kinase/mammalian-target-of-rapamycin (AMPK/mTOR) pathway to control metabolism. Since LKB1 is also required for polarized epithelial cells to resist hyperplasia it is anticipated to function through additional mechanisms. Recently, Yes-associated protein (Yap) has emerged as a transcriptional co-activator that modulates tissue homeostasis in response to cell-cell contact. Thus this study examined a possible connection between Yap and LKB1. Restoration of LKB1 expression in HeLa cells, which lack this tumor suppressor, or shRNA knockdown of LKB1 in NTERT immortalized keratinocytes, demonstrated that LKB1 promotes Yap phosphorylation, nuclear exclusion, and proteasomal degradation. The ability of phosphorylation-defective Yap mutants to rescue LKB1 phenotypes, such as reduced cell proliferation and cell size, suggest that Yap inhibition contributes to LKB1 tumor suppressor function(s). However, failure of Lats1/2 knockdown to suppress LKB1-mediated Yap regulation suggested that LKB1 signals to Yap via a non-canonical pathway. Additionally, LKB1 inhibited Yap independently of either AMPK or mTOR activation. These findings reveal a novel mechanism whereby LKB1 may restrict cancer cell growth via the inhibition of Yap.
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影响因子：
8
作者：
Gill RK;Yang SH;Meerzaman D;Mechanic LE;Bowman ED;Jeon HS;Roy Chowdhuri S;Shakoori A;Dracheva T;Hong KM;Fukuoka J;Zhang JH;Harris CC;Jen J
通讯作者：
Jen J
影响因子：
4.8
作者：
Castro, AF;Rebhun, JF;Quilliam, LA
通讯作者：
Quilliam, LA
E-钙黏着蛋白的分离激活RAP1 GTPase。
影响因子：
4
作者：
Asuri, Sirisha;Yan, Jingliang;Paranavitana, Nivanka C.;Quilliam, Lawrence A.
通讯作者：
Quilliam, Lawrence A.
影响因子：
16
作者：
Basu, S;Totty, NF;Downward, J
通讯作者：
Downward, J
影响因子：
10.5
作者：
Lian, Ian;Kim, Joungmok;Guan, Kun-Liang
通讯作者：
Guan, Kun-Liang