Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis.
Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis.
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DOI：
10.1038/ncomms9859
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发表时间：
2015-11-30
影响因子：
16.6
通讯作者：
Ohh M
中科院分区：
文献类型：
--
作者：
Bunda S;Burrell K;Heir P;Zeng L;Alamsahebpour A;Kano Y;Raught B;Zhang ZY;Zadeh G;Ohh M
Ras通过Src激酶在开关I区域内32位的保守酪氨酸上磷酸化。这种磷酸化抑制效应Raf的结合，同时促进GTP酶激活蛋白（GAP）和GTP水解的参与。在这里，我们确定SHP 2作为普遍表达的酪氨酸磷酸酶，优先结合和去磷酸化Ras，以增加其与Raf的关联，并激活下游增殖Ras/ERK/MAPK信号转导。与正常星形胶质细胞相比，在从多形性胶质母细胞瘤（GBM）易感性H-Ras（12 V）敲入小鼠分离的星形胶质细胞中以及在神经胶质瘤细胞系和表现出过度活跃的Ras的患者来源的GBM标本中，SHP 2活性升高。药理学抑制SHP 2活性可减弱NOD/SCID小鼠的细胞增殖、软琼脂集落形成和原位GBM生长，并在自发转基因胶质瘤小鼠模型中减缓低级别星形细胞瘤向GBM的进展。这些结果确定SHP 2是Ras的直接激活剂，也是由以前“不可治疗”的致癌或过度活跃的Ras驱动的癌症的潜在治疗靶点。 在许多癌症中发现了导致下游Mek/Erk途径活化的异常Ras信号传导。在这里，作者表明磷酸酶SHP 2使Ras去磷酸化，导致Ras活性增加，并且在胶质母细胞瘤中发现SHP 2活性增加。
Ras is phosphorylated on a conserved tyrosine at position 32 within the switch I region via Src kinase. This phosphorylation inhibits the binding of effector Raf while promoting the engagement of GTPase-activating protein (GAP) and GTP hydrolysis. Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. In comparison to normal astrocytes, SHP2 activity is elevated in astrocytes isolated from glioblastoma multiforme (GBM)-prone H-Ras(12V) knock-in mice as well as in glioma cell lines and patient-derived GBM specimens exhibiting hyperactive Ras. Pharmacologic inhibition of SHP2 activity attenuates cell proliferation, soft-agar colony formation and orthotopic GBM growth in NOD/SCID mice and decelerates the progression of low-grade astrocytoma to GBM in a spontaneous transgenic glioma mouse model. These results identify SHP2 as a direct activator of Ras and a potential therapeutic target for cancers driven by a previously ‘undruggable' oncogenic or hyperactive Ras. Aberrant Ras signalling resulting in downstream Mek/Erk pathway activation is found in many cancers. Here, the authors show that the phosphatase SHP2 dephosphorylates Ras resulting in increased Ras activity, and that increased SHP2 activity is found in glioblastomas.