Uncoupling of the LKB1-AMPKalpha energy sensor pathway by growth factors and oncogenic BRAF.
Uncoupling of the LKB1-AMPKalpha energy sensor pathway by growth factors and oncogenic BRAF.
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DOI：
10.1371/journal.pone.0004771
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Recio JA
中科院分区：
文献类型：
--
作者：
Esteve-Puig R;Canals F;Colomé N;Merlino G;Recio JA
了解黑色素瘤发生和发展的生化机制对于治疗干预至关重要。LKB1是一种多任务的丝氨酸/苏氨酸蛋白激酶，它能磷酸化AMPK，在代谢应激条件下控制细胞的生长和凋亡。此外，LKB1Ser428以依赖Ras-ERK1/2-p90RSK途径的方式被磷酸化。然而，RAS通路和LKB1之间的联系大多是未知的。利用紫外线诱导的HGF转基因小鼠黑色素瘤模型，研究HGF信号、Ras通路和PI3K通路在黑色素瘤中的相互作用，我们鉴定LKB1是一种被HGF诱导信号直接修饰的蛋白质。多种分子技术和组织培养表明，LKB1Ser428(在小鼠中为Ser431)在BRAFV600E突变的黑色素瘤细胞系和具有高RAS途径活性的自发肿瘤中被结构性磷酸化。有趣的是，BRAFV600E突变黑色素瘤细胞对LKB1-AMPK-mTOR途径介导的代谢应激反应非常有限。在这里，我们首次证明了包括BRAFV600E突变在内的RAS通路的激活促进了AMPK与LKB1的解偶联，其机制似乎独立于LKB1Ser428的磷酸化。值得注意的是，BRAFV600E突变黑色素瘤细胞中RAS途径的抑制恢复了复合体的形成，并挽救了LKB1-AMPKα代谢应激诱导的反应，与促凋亡蛋白Bad和Bim协同增加了细胞凋亡，并下调了Mcl-1的表达。这些数据表明，生长因子治疗，特别是致癌的BRAFV600E诱导了LKB1-AMPKα复合体的解偶联，同时提供了一种可能的细胞增殖机制，即参与细胞生长和细胞分裂，以响应有丝分裂刺激和抵抗肿瘤细胞的低能量条件。重要的是，这一机制揭示了治疗干预的新水平，尤其与含有非调控的RAS-ERK1/2通路的肿瘤相关。
Understanding the biochemical mechanisms contributing to melanoma development and progression is critical for therapeutical intervention. LKB1 is a multi-task Ser/Thr kinase that phosphorylates AMPK controlling cell growth and apoptosis under metabolic stress conditions. Additionally, LKB1Ser428 becomes phosphorylated in a RAS-Erk1/2-p90RSK pathway dependent manner. However, the connection between the RAS pathway and LKB1 is mostly unknown. Using the UV induced HGF transgenic mouse melanoma model to investigate the interplay among HGF signaling, RAS pathway and PI3K pathway in melanoma, we identified LKB1 as a protein directly modified by HGF induced signaling. A variety of molecular techniques and tissue culture revealed that LKB1Ser428 (Ser431 in the mouse) is constitutively phosphorylated in BRAFV600E mutant melanoma cell lines and spontaneous mouse tumors with high RAS pathway activity. Interestingly, BRAFV600E mutant melanoma cells showed a very limited response to metabolic stress mediated by the LKB1-AMPK-mTOR pathway. Here we show for the first time that RAS pathway activation including BRAFV600E mutation promotes the uncoupling of AMPK from LKB1 by a mechanism that appears to be independent of LKB1Ser428 phosphorylation. Notably, the inhibition of the RAS pathway in BRAFV600E mutant melanoma cells recovered the complex formation and rescued the LKB1-AMPKα metabolic stress-induced response, increasing apoptosis in cooperation with the pro-apoptotic proteins Bad and Bim, and the down-regulation of Mcl-1. These data demonstrate that growth factor treatment and in particular oncogenic BRAFV600E induces the uncoupling of LKB1-AMPKα complexes providing at the same time a possible mechanism in cell proliferation that engages cell growth and cell division in response to mitogenic stimuli and resistance to low energy conditions in tumor cells. Importantly, this mechanism reveals a new level for therapeutical intervention particularly relevant in tumors harboring a deregulated RAS-Erk1/2 pathway.
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