The MEK-ERK pathway is necessary for serine phosphorylation of mitochondrial STAT3 and Ras-mediated transformation.
The MEK-ERK pathway is necessary for serine phosphorylation of mitochondrial STAT3 and Ras-mediated transformation.
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DOI：
10.1371/journal.pone.0083395
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Levy DE
中科院分区：
文献类型：
--
作者：
Gough DJ;Koetz L;Levy DE
RasGTP酶的激活突变是人类癌症中最常见的致癌病变。类似地，在大多数人类癌症中观察到升高的STAT 3表达和/或磷酸化。我们最近发现激活的Ras需要线粒体而不是STAT 3的核活性来支持细胞转化。STAT 3的这种线粒体活性由STAT 3羧基端丝氨酸727（S727）上的磷酸化支持。在这项研究中，我们发现H-Ras癌蛋白参与MEK-ERK途径来驱动S727上STAT 3的磷酸化，而磷酸肌醇3-激酶（PI 3 K）和mTOR活性是多余的。此外，MEK的药理学抑制减少了H-、K-或N-Ras的转化。然而，表达线粒体限制性STAT 3（在S727处具有磷酸模拟突变）的细胞对ERK途径的抑制具有部分抵抗力，在MEK抑制剂的存在下表现出对锚定非依赖性细胞生长的部分拯救。这项研究表明，MEK-ERK途径是激活Ras诱导的S727上STAT 3磷酸化所必需的，STAT 3 S727磷酸化的抑制有助于MEK抑制剂的抗癌潜力，并且线粒体STAT 3是细胞转化期间Ras-MEK-ERK轴的关键底物之一。
Activating mutations in the RasGTPases are the most common oncogenic lesions in human cancer. Similarly, elevated STAT3 expression and/or phosphorylation are observed in the majority of human cancers. We recently found that activated Ras requires a mitochondrial rather than a nuclear activity of STAT3 to support cellular transformation. This mitochondrial activity of STAT3 was supported by phosphorylation on serine 727 (S727) in the carboxyl-terminus of STAT3. In this study we show that the H-Ras oncoprotein engages the MEK-ERK pathway to drive phosphorylation of STAT3 on S727, while phosphoinositide 3-kinase (PI3K) and mTOR activity were superfluous. Moreover, pharmacological inhibition of MEK reduced transformation by H-, K- or N-Ras. However, cells expressing a mitochondrially restricted STAT3 with a phospho-mimetic mutation at S727 were partially resistant to inhibition of the ERK pathway, exhibiting a partial rescue of anchorage-independent cell growth in the presence of MEK inhibitor. This study shows that the MEK-ERK pathway is required for activated Ras-induced phosphorylation of STAT3 on S727, that inhibition of STAT3 S727 phosphorylation contributes to the anti-oncogenic potential of MEK inhibitors, and that mitochondrial STAT3 is one of the critical substrates of the Ras-MEK-ERK- axis during cellular transformation.
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影响因子：
9.5
作者：
Boengler K;Hilfiker-Kleiner D;Heusch G;Schulz R
通讯作者：
Schulz R
DOI：
10.1038/nrm3255
发表时间：
2011-12-22
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
15.9
作者：
Levy, DE;Lee, CK
通讯作者：
Lee, CK
影响因子：
50.3
作者：
Bollrath, Julia;Phesse, Toby J.;Greten, Florian R.
通讯作者：
Greten, Florian R.
影响因子：
15.9
作者：
Frank, DA;Mahajan, S;Ritz, J
通讯作者：
Ritz, J