The mitogen-activated protein kinases (MAPKs) regulate a variety of cellular processes. The three main MAPK cascades are the extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 kinases. A typical MAPK cascade is composed of MAP3K-MAP2K-MAPK kinases that are held by scaffold proteins. Scaffolds function to assemble the protein tier and contribute to the specificity and efficacy of signal transmission. WD repeat domain 62 (WDR62) is a JNK scaffold protein, interacting with JNK, MKK7, and several MAP3Ks. The loss of WDR62 in human leads to microcephaly and pachygyria. Yet the role of WDR62 in cellular function is not fully studied. We used the CRISPR/Cas9 and short hairpin RNA approaches to establish a human breast cancer cell line MDA-MB-231 with WDR62 loss of function and studied the consequence to JNK signaling. In growing cells, WDR62 is responsible for the basal expression of c-Jun. In stressed cells, WDR62 specifically mediates TNFα-dependent JNK activation through the association with both the adaptor protein, TNF receptor-associated factor 2 (TRAF2), and the MAP3K protein, mixed lineage kinase 3. TNFα-dependent JNK activation is mediated by WDR62 in HCT116 and HeLa cell lines as well. MDA-MB-231 WDR62-knockout cells display increased resistance to TNFα-induced cell death. Collectively, WDR62 coordinates the TNFα receptor signaling pathway to JNK activation through association with multiple kinases and the adaptor protein TRAF2.

译文

丝裂原活化蛋白激酶 (MAPKs) 调节多种细胞过程。三个主要的MAPK级联是细胞外信号调节激酶 (ERK),c 6月N端激酶 (JNK) 和p38激酶。典型的MAPK级联反应由支架蛋白持有的MAP3K-MAP2K-MAPK激酶组成。支架的功能是组装蛋白质层,并有助于信号传递的特异性和有效性。WD重复结构域62 (WDR62) 是一种JNK支架蛋白,与JNK、MKK7和几个map3k相互作用。人类中WDR62的丢失会导致小头畸形和粗大症。然而,WDR62在细胞功能中的作用尚未得到充分研究。我们使用CRISPR/Cas9和短发夹RNA方法建立了具有WDR62功能丧失的人乳腺癌细胞系MDA-MB-231,并研究了JNK信号传导的后果。在生长的细胞中,WDR62负责c-6月的基础表达在应激细胞中,WDR62通过与衔接蛋白,TNF受体相关因子2 (TRAF2) 和MAP3K蛋白混合谱系激酶3结合,特异性介导TNF α 依赖性JNK激活。Tnf α 依赖性JNK激活也由HCT116和HeLa细胞系中的WDR62介导。MDA-MB-231 WDR62-knockout细胞显示对tnf α 诱导的细胞死亡的抗性增加。总的来说,WDR62通过与多种激酶和衔接蛋白traf2结合,协调tnf α 受体信号通路与JNK激活。

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