Li Shang-Ze, Zhang Ze-Yan, Chen Jie, Dong Ming-You, Du Xue-Hua, Gao Jie, Shu Qi-Peng, Li Chao, Liang Xin-Yi, Ding Zhi-Hao, Du Run-Lei, Wang Junli, Zhang Xiao-Dong
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, 430072, Wuhan, Hubei, China.
School of Medicine, Chongqing University, 400030, Chongqing, China.
Cell Death Discov. 2022 Jan 10;8(1):4. doi: 10.1038/s41420-021-00774-9.
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.
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转录共激活因子结合来调节分化和增殖，但负责SRF调节的分子机制仍不清楚。在这里，我们表明，在人和小鼠细胞中促进SRF/ELK信号传导需要Nemo样激酶（NLK）。发现NLK与SRF在丝氨酸残基101/103处相互作用并使其磷酸化，这反过来增强了SRF与ELK之间的关联。SRF/ELK亲和力的增强拮抗了SRF/MKL途径并在体外抑制了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了肥大生长，导致肌肉和体重增加的表型。我们提出，NLK对SRF的磷酸化和MAPK对ELK的磷酸化都是RAS/ELK信号传导所必需的，这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。
