NLK is required for Ras/ERK/SRF/ELK signaling to tune skeletal muscle development by phosphorylating SRF and antagonizing the SRF/MKL pathway.
NLK is required for Ras/ERK/SRF/ELK signaling to tune skeletal muscle development by phosphorylating SRF and antagonizing the SRF/MKL pathway.
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Ras/ERK/SRF/ELK 信号传导需要 NLK，通过磷酸化 SRF 和拮抗 SRF/MKL 途径来调节骨骼肌发育
DOI：
10.1038/s41420-021-00774-9
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发表时间：
2022-01-10
影响因子：
7
通讯作者：
Zhang XD
中科院分区：
文献类型：
--
作者：
Li SZ;Zhang ZY;Chen J;Dong MY;Du XH;Gao J;Shu QP;Li C;Liang XY;Ding ZH;Du RL;Wang J;Zhang XD
血清反应因子（SRF）通过与RhoA-肌动蛋白激活的MKL或Ras-MAPK激活的ELK转录辅激活因子结合来调节分化和增殖，但负责SRF调节的分子机制尚不清楚。在这里，我们表明，Nemo样激酶（NLK）是促进人类和小鼠细胞中SRF/ELK信号传导所必需的。发现NLK与SRF在丝氨酸残基101/103处相互作用并磷酸化，这反过来增强了SRF与ELK之间的缔合。增强的SRF/ELK亲和力拮抗SRF/MKL通路，并抑制小鼠成肌细胞的分化。在骨骼肌特异性Nlk条件性敲除小鼠模型中，形成的肌肉肌纤维经历肥大生长，导致肌肉和体重表型增加。我们认为NLK对SRF的磷酸化和MAPK对ELKs的磷酸化都是RAS/ELK信号传导所必需的，证实了这一古老途径的重要性，并确定了NLK在体内调节肌肉发育中的重要作用。
Serum response factor (SRF) regulates differentiation and proliferation by binding to RhoA-actin-activated MKL or Ras-MAPK-activated ELK transcriptional coactivators, but the molecular mechanisms responsible for SRF regulation remain unclear. Here, we show that Nemo-like kinase (NLK) is required for the promotion of SRF/ELK signaling in human and mouse cells. NLK was found to interact with and phosphorylate SRF at serine residues 101/103, which in turn enhanced the association between SRF and ELK. The enhanced affinity of SRF/ELK antagonized the SRF/MKL pathway and inhibited mouse myoblast differentiation in vitro. In a skeletal muscle-specific Nlk conditional knockout mouse model, forming muscle myofibers underwent hypertrophic growth, resulting in an increased muscle and body mass phenotype. We propose that both phosphorylation of SRF by NLK and phosphorylation of ELKs by MAPK are required for RAS/ELK signaling, confirming the importance of this ancient pathway and identifying an important role for NLK in modulating muscle development in vivo.
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DOI：
10.1038/nrm2890
发表时间：
2010-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
2.9
作者：
Zhu, Gao-Hui;Huang, Jiayi;Bi, Yang;Su, Yuxi;Tang, Yi;He, Bai-Cheng;He, Yun;Luo, Jinyong;Wang, Yi;Chen, Liang;Zuo, Guo-Wei;Jiang, Wei;Luo, Qing;Shen, Jikun;Liu, Bo;Zhang, Wen-Li;Shi, Qiong;Zhang, Bing-Qiang;Kang, Quan;Zhu, Jing;Tian, Jie;Luu, Hue H.;Haydon, Rex C.;Chen, Yuan;He, Tong-Chuan
通讯作者：
He, Tong-Chuan
影响因子：
5.3
作者：
Zaromytidou, Alexia-Ileana;Miralles, Francesc;Treisman, Richard
通讯作者：
Treisman, Richard
影响因子：
3.3
作者：
Ishitani S;Inaba K;Matsumoto K;Ishitani T
通讯作者：
Ishitani T
DOI：
10.1083/jcb.200106008
发表时间：
2002-02-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Schratt G;Philippar U;Berger J;Schwarz H;Heidenreich O;Nordheim A
通讯作者：
Nordheim A