ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma.
ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma.
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ERK 介导的磷酸化调节 SOX10 sumoylation 并靶向突变 BRAF 黑色素瘤中的表达
DOI：
10.1038/s41467-017-02354-x
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发表时间：
2018-01-02
影响因子：
16.6
通讯作者：
Shao Y
中科院分区：
文献类型：
--
作者：
Han S;Ren Y;He W;Liu H;Zhi Z;Zhu X;Yang T;Rong Y;Ma B;Purwin TJ;Ouyang Z;Li C;Wang X;Wang X;Yang H;Zheng Y;Aplin AE;Liu J;Shao Y
在人突变型BRAF黑色素瘤细胞中，干性转录因子FOXD 3通过抑制ERK 1/2信号传导迅速诱导，并介导对RAF抑制剂的适应性抗性。然而，ERK信号控制FOXD 3表达的潜在机制仍不清楚。在这里，我们表明，SOX 10是必要的和足够的RAF肿瘤诱导的突变BRAF黑色素瘤细胞表达FOXD 3。SOX 10通过与FOXD 3启动子中的调节元件结合来激活FOXD 3的转录。ERK对SOX 10的磷酸化通过干扰SOX 10在K55处的sumoylation来抑制其对多个靶基因的转录活性，K55是SOX 10转录活性所必需的。最后，SOX 10的耗竭在体外和体内使突变BRAF黑素瘤细胞对RAF抑制剂敏感。因此，我们的工作发现了一种新的磷酸化依赖性的调控机制，SOX 10的转录活性和完成ERK 1/2/SOX 10/FOXD 3/ERBB 3轴介导的适应性耐药突变BRAF黑色素瘤细胞RAF抑制剂。
In human mutant BRAF melanoma cells, the stemness transcription factor FOXD3 is rapidly induced by inhibition of ERK1/2 signaling and mediates adaptive resistance to RAF inhibitors. However, the mechanism underlying ERK signaling control of FOXD3 expression remains unknown. Here we show that SOX10 is both necessary and sufficient for RAF inhibitor-induced expression of FOXD3 in mutant BRAF melanoma cells. SOX10 activates the transcription of FOXD3 by binding to a regulatory element in FOXD3 promoter. Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity. Finally, depletion of SOX10 sensitizes mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo. Thus, our work discovers a novel phosphorylation-dependent regulatory mechanism of SOX10 transcription activity and completes an ERK1/2/SOX10/FOXD3/ERBB3 axis that mediates adaptive resistance to RAF inhibitors in mutant BRAF melanoma cells.
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Fbxw7alpha 通过泛素化介导的降解调节 SOX10 稳定性，从而调节黑色素瘤细胞迁移。
影响因子：
--
作者：
Lv XB;Wu W;Tang X;Wu Y;Zhu Y;Liu Y;Cui X;Chu J;Hu P;Li J;Guo Q;Cai Z;Wu J;Hu K;Ouyang N
通讯作者：
Ouyang N
影响因子：
8
作者：
Basile, K. J.;Abel, E. V.;Aplin, A. E.
通讯作者：
Aplin, A. E.
影响因子：
11.2
作者：
Cronin JC;Watkins-Chow DE;Incao A;Hasskamp JH;Schönewolf N;Aoude LG;Hayward NK;Bastian BC;Dummer R;Loftus SK;Pavan WJ
通讯作者：
Pavan WJ
DOI：
10.1523/jneurosci.2546-10.2010
发表时间：
2010-08-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chew LJ;Coley W;Cheng Y;Gallo V
通讯作者：
Gallo V
影响因子：
82.9
作者：
Hata AN;Niederst MJ;Archibald HL;Gomez-Caraballo M;Siddiqui FM;Mulvey HE;Maruvka YE;Ji F;Bhang HE;Krishnamurthy Radhakrishna V;Siravegna G;Hu H;Raoof S;Lockerman E;Kalsy A;Lee D;Keating CL;Ruddy DA;Damon LJ;Crystal AS;Costa C;Piotrowska Z;Bardelli A;Iafrate AJ;Sadreyev RI;Stegmeier F;Getz G;Sequist LV;Faber AC;Engelman JA
通讯作者：
Engelman JA