Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Oncogene. 2013 Aug 29;32(35):4100-9. doi: 10.1038/onc.2012.431. Epub 2012 Oct 1.
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. As 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 short-hairpin RNA 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.
肝激酶 B1（LKB1）肿瘤抑制因子通过调节细胞代谢和顶端-基底极性来抑制细胞生长。LKB1 限制细胞生长的最佳理解机制是通过激活 AMP 激活蛋白激酶/哺乳动物雷帕霉素靶蛋白（AMPK/mTOR）途径来控制代谢。由于 LKB1 对于极化上皮细胞抵抗增生也是必需的，因此预计它将通过其他机制发挥作用。最近，Yes 相关蛋白（Yap）已成为一种转录共激活因子，可响应细胞间接触来调节组织稳态。因此，本研究检查了 Yap 和 LKB1 之间可能存在的联系。在缺乏这种肿瘤抑制因子的 HeLa 细胞中恢复 LKB1 的表达，或在 NTERT 永生化角质形成细胞中用短发夹 RNA 敲低 LKB1，证明 LKB1 促进 Yap 磷酸化、核排斥和蛋白酶体降解。磷酸化缺陷的 yap 突变体能够拯救 LKB1 表型，如降低细胞增殖和细胞大小，这表明 yap 抑制有助于 LKB1 肿瘤抑制因子的功能。然而，Lats1/2 敲低未能抑制 LKB1 介导的 yap 调节表明，LKB1 通过非经典途径向 yap 发出信号。此外，LKB1 抑制 yap 不依赖于 AMPK 或 mTOR 的激活。这些发现揭示了一种新的机制，即 LKB1 可能通过抑制 yap 来限制癌细胞的生长。
