Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF.
Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF.
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DOI：
10.1126/scisignal.2001936
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发表时间：
2011-09-13
影响因子：
7.3
通讯作者：
Recio JA
中科院分区：
文献类型：
--
作者：
Andreu-Pérez P;Esteve-Puig R;de Torre-Minguela C;López-Fauqued M;Bech-Serra JJ;Tenbaum S;García-Trevijano ER;Canals F;Merlino G;Avila MA;Recio JA
RAS到细胞外信号调节激酶（ERK）信号转导级联对细胞增殖、分化和存活至关重要。虽然有许多生长因子激活RAS-ERK通路，但它们对ERK信号的振幅和持续时间有不同的影响，因此对生物学后果也有不同的影响。例如，与表皮生长因子（EGF）相比，神经生长因子在PC12细胞中引起更大、更持续的ERK磷酸化增加，刺激PC12细胞分化，而EGF刺激PC12细胞增殖。在这里，我们发现蛋白精氨酸甲基化限制了来自不同物种的不同细胞类型中特定生长因子引发的ERK1/2信号。我们发现ERK1/2磷酸化的这种限制依赖于蛋白精氨酸甲基转移酶5 （PRMT5）对RAF蛋白的甲基化。prmt5依赖性甲基化增强了活化的CRAF和BRAF的降解，从而降低了它们的催化活性。抑制PRMT5活性或抑制无法甲基化的RAF突变体的表达，不仅影响ERK对生长因子的磷酸化幅度和持续时间，还将PC12细胞对EGF的反应从增殖转向分化。RAS通路内的这种额外水平的调节可能导致治疗干预的新靶点的确定。
The RAS to extracellular signal–regulated kinase (ERK) signal transduction cascade is crucial to cell proliferation, differentiation, and survival. Although numerous growth factors activate the RAS-ERK pathway, they can have different effects on the amplitude and duration of the ERK signal and, therefore, on the biological consequences. For instance, nerve growth factor, which elicits a larger and more sustained increase in ERK phosphorylation in PC12 cells than does epidermal growth factor (EGF), stimulates PC12 cell differentiation, whereas EGF stimulates PC12 cell proliferation. Here, we show that protein arginine methylation limits the ERK1/2 signal elicited by particular growth factors in different cell types from various species. We found that this restriction in ERK1/2 phosphorylation depended on methylation of RAF proteins by protein arginine methyltransferase 5 (PRMT5). PRMT5-dependent methylation enhanced the degradation of activated CRAF and BRAF, thereby reducing their catalytic activity. Inhibition of PRMT5 activity or expression of RAF mutants that could not be methylated not only affected the amplitude and duration of ERK phosphorylation in response to growth factors but also redirected the response of PC12 cells to EGF from proliferation to differentiation. This additional level of regulation within the RAS pathway may lead to the identification of new targets for therapeutic intervention.
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影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
11.2
作者：
Maloney, Alison;Clarke, Paul A.;Workman, Paul
通讯作者：
Workman, Paul
影响因子：
4.8
作者：
Kao, SC;Jaiswal, RK;Landreth, GE
通讯作者：
Landreth, GE
影响因子：
4.8
作者：
Friesen, WJ;Wyce, A;Dreyfuss, G
通讯作者：
Dreyfuss, G
DOI：
10.1016/j.biocel.2003.11.016
发表时间：
2004-11-01
影响因子：
4
作者：
Avila, MA;García-Trevijano, ER;Mato, JM
通讯作者：
Mato, JM