DGKA interacts with SRC/FAK to promote the metastasis of non-small cell lung cancer
DGKA interacts with SRC/FAK to promote the metastasis of non-small cell lung cancer
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DGKA与SRC/FAK相互作用促进非小细胞肺癌转移
DOI：
10.1016/j.canlet.2022.215585
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发表时间：
2022-02-08
期刊：
影响因子：
9.7
通讯作者：
Yun, Jingping
中科院分区：
文献类型：
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作者：
Fu, Lingyi;Deng, Ru;Yun, Jingping
转移是肺癌高死亡率的原因，但其潜在的分子机制知之甚少。在这里，我们证明了二酰基甘油激酶α（DGKA）的表达在非小细胞肺癌（NSCLC）的转移灶中升高，并与生存率低相关。机制研究揭示了DGKA，原癌基因酪氨酸蛋白激酶Src（SRC）和粘着斑激酶1（FAK）蛋白之间的直接物理相互作用以及相互调节。DGKA的C末端结构域负责SRC SH 3结构域结合，而DGKA的催化结构域与FAK的FREM结构域相互作用。DGKA磷酸化SRC蛋白Tyr 416和FAK蛋白Tyr 397，形成并激活DGKA/SRC/FAK复合物，从而启动下游WNT/beta-catenin和VEGF信号通路，促进上皮-间质转化（EMT）和血管生成，导致NSCLC转移。DGKA敲低抑制NSCLC细胞的体外侵袭表型。DGKA的药理学消融抑制NSCLC细胞的体内转移，并且这种抑制被DGKA的过表达逆转。这些结果表明，DGKA是一个潜在的预后生物标志物，也是一个有前途的治疗靶点，特别是当有淋巴结转移或远处转移时。
Metastasis is responsible for the high mortality rate of lung cancer, but its underlying molecular mechanisms are poorly understood. Here, we demonstrated that the expression of diacylglycerol kinase alpha (DGKA) was elevated in the metastatic lesions of non-small cell lung cancer (NSCLC) and correlated with poor survival. Mechanistic studies revealed a direct physical interaction as well as a mutual regulation among DGKA, proto-oncogene tyrosine-protein kinase Src (SRC), and focal adhesion kinase 1 (FAK) proteins. The C-terminal domain of DGKA was responsible for the SRC SH3 domain binding, while the catalytic domain of DGKA inter-acted with the FREM domain of FAK. DGKA phosphorylated the SRC protein at Tyr416 and the FAK protein at Tyr397 to form and activate the DGKA/SRC/FAK complex, thus initiating the downstream WNT/beta-catenin and VEGF signaling pathways, promoting epithelial-mesenchymal transition (EMT) and angiogenesis, and resulting in the metastasis of NSCLC. DGKA knockdown inhibited the invasive phenotype of NSCLC cells in vitro. Phar-macologic ablation of DGKA inhibited the metastasis of NSCLC cells in vivo, and this was reversed by the overexpression of DGKA. These results suggested that DGKA was a potential prognostic biomarker as well as a promising therapeutic target for NSCLC, especially when there was lymphatic or distant metastasis.