抑癌基因 RASSF1A 可防止哺乳动物 STE20 样激酶 MST1 和 MST2 的去磷酸化。
The tumor suppressor RASSF1A prevents dephosphorylation of the mammalian STE20-like kinases MST1 and MST2.
机构信息
Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California 91010, USA.
出版信息
J Biol Chem. 2011 Feb 25;286(8):6253-61. doi: 10.1074/jbc.M110.178210. Epub 2011 Jan 3.
Abstract
The RASSF1A tumor suppressor protein interacts with the pro-apoptotic mammalian STE20-like kinases MST1 and MST2 and induces their autophosphorylation and activation, but the mechanism of how RASSF1A activates MST1/2 is unclear. Okadaic acid treatment and PP2A knockdown promoted MST1/2 phosphorylation. Data from dephosphorylation assays and reduced activation of MST1/2 seen after RASSF1A depletion suggest that dephosphorylation of MST1/2 on Thr-183 and Thr-180 by PP2A is prevented by RASSF1A, shifting the balance of MST1/2 to the activated autophosphorylated form. In addition to preventing dephosphorylation, RASSF1A also stabilized the MST2 protein. Through binding to MST1/2, RASSF1A supports maintenance of MST1/2 phosphorylation, promoting an active state of the MST kinases and favoring induction of apoptosis. This is one of the first examples of a tumor suppressor acting as an inhibitor of a specific dephosphorylation pathway.
摘要
RASSF1A 肿瘤抑制蛋白与促凋亡的哺乳动物 STE20 样激酶 MST1 和 MST2 相互作用，并诱导其自身磷酸化和激活，但 RASSF1A 如何激活 MST1/2 的机制尚不清楚。冈田酸处理和 PP2A 敲低促进了 MST1/2 的磷酸化。磷酸化实验数据和 RASSF1A 耗竭后观察到的 MST1/2 活性降低表明，RASSF1A 阻止了 PP2A 对 Thr-183 和 Thr-180 的 MST1/2 去磷酸化，使 MST1/2 向激活的自身磷酸化形式转变。除了防止去磷酸化，RASSF1A 还稳定了 MST2 蛋白。通过与 MST1/2 结合，RASSF1A 支持 MST1/2 磷酸化的维持，促进 MST 激酶的活性状态，并有利于诱导细胞凋亡。这是肿瘤抑制因子作为特定去磷酸化途径抑制剂的第一个例子之一。
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