Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells.
Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells.
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DOI：
10.1111/j.1471-4159.2010.07049.x
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发表时间：
2010-12
影响因子：
4.7
通讯作者：
Sontag E
中科院分区：
文献类型：
--
作者：
Sontag JM;Nunbhakdi-Craig V;Mitterhuber M;Ogris E;Sontag E
神经炎性改变是许多神经退行性疾病的主要特征。亮氨酸羧基甲基转移酶LCMT 1对蛋白磷酸酶2A（PP 2A）催化C亚基的甲基化和甲基酯酶PME-1对PP 2A催化C亚基的去甲基化是PP 2A的重要调控机制。它调节含有Bα亚基的PP 2 A全酶的形成，该亚基使关键神经元细胞骨架蛋白（包括tau）去磷酸化。值得注意的是，我们已经报道了LCMT 1，甲基化C和Bα表达水平在阿尔茨海默病影响的脑区下调。在这里，我们发现在培养的N2 a神经母细胞瘤细胞中LCMT 1的表达增强，这增加了内源性甲基化C和Bα水平，诱导F-肌动蛋白组织的变化。它促进N2 a细胞分化后的血清非依赖性神经突发生和扩展的tau阳性过程的发展。这些刺激作用可以通过LCMT 1敲低和S-腺苷高半胱氨酸（甲基化反应的抑制剂）来消除。PME-1和甲基化位点L309Δ C亚基突变体的表达可降低细胞内甲基化C和Bα水平，阻断N2 a细胞分化和LCMT 1介导的神经突形成。最后，N2 a细胞中Bα的诱导性和非诱导性敲低抑制了过程生长。总而言之，我们的研究结果建立了PP 2A甲基化和神经突样过程发育之间的新机制联系。
Neuritic alterations are a major feature of many neurodegenerative disorders. Methylation of protein phosphatase 2A (PP2A) catalytic C subunit by the leucine carboxyl methyltransferase LCMT1, and demethylation by the methylesterase PME-1, is a critical PP2A regulatory mechanism. It modulates the formation of PP2A holoenzymes containing the Bα subunit, which dephosphorylate key neuronal cytoskeletal proteins, including tau. Significantly, we have reported that LCMT1, methylated C and Bα expression levels are down-regulated in Alzheimer disease-affected brain regions. Here, we show that enhanced expression of LCMT1 in cultured N2a neuroblastoma cells, which increases endogenous methylated C and Bα levels, induces changes in F-actin organization. It promotes serum-independent neuritogenesis and development of extended tau-positive processes upon N2a cell differentiation. These stimulatory effects can be abrogated by LCMT1 knockdown and S-adenosylhomocysteine, an inhibitor of methylation reactions. Expression of PME-1 and the methylation-site L309Δ C subunit mutant, which decrease intracellular methylated C and Bα levels, block N2a cell differentiation and LCMT1-mediated neurite formation. Lastly, inducible and non-inducible knockdown of Bα in N2a cells inhibit process outgrowth. Altogether, our results establish a novel mechanistic link between PP2A methylation and development of neurite-like processes.
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蛋白质磷酸酶2a的新型池与微管有关，并在细胞周期中受到调节。
影响因子：
7.8
作者：
Sontag, E;Nunbhakdi-Craig, V;Bloom, G S;Mumby, M C
通讯作者：
Mumby, M C
DOI：
10.1523/jneurosci.2816-08.2008
发表时间：
2008-11-05
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Sontag JM;Nunbhakdi-Craig V;Montgomery L;Arning E;Bottiglieri T;Sontag E
通讯作者：
Sontag E
影响因子：
4.8
作者：
Leulliot, N;Quevillon-Cheruel, S;van Tilbeurgh, H
通讯作者：
van Tilbeurgh, H
影响因子：
4.8
作者：
Brandt, Nicola;Franke, Kristin;Schumacher, Stefan
通讯作者：
Schumacher, Stefan
影响因子：
4.8
作者：
Lee, Jocelyn A.;Pallas, David C.
通讯作者：
Pallas, David C.