生物
MAPK/ERK通路
细胞周期蛋白依赖激酶1
细胞生长
细胞周期蛋白依赖激酶2
癌症研究
细胞生物学
下调和上调
信号转导
激酶
癌细胞
调节器
细胞周期
细胞
癌症
蛋白激酶A
生物化学
遗传学
基因
作者
Jinhuan Wu,Yuping Chen,R. Li,Y.-t. Guan,M H Chen,Hui Yin,Xiaoning Yang,Mingpeng Jin,Bingsong Huang,Xin Ding,Jie Yang,Zhe Wang,Yiming He,Qianwen Wang,Jian Luo,Ping Wang,Zhiyong Mao,Michael S.Y. Huen,Zhenkun Lou,Jian Yuan
标识
DOI:10.1083/jcb.202203005
摘要
The EGFR-RAS-ERK pathway is one of the most important signaling cascades in cell survival, growth, and proliferation. Aberrant activation of this pathway is a common mechanism in various cancers. Here, we report that CDK2 is a novel regulator of the ERK pathway via USP37 deubiquitinase (DUB). Mechanistically, CDK2 phosphorylates USP37, which is required for USP37 DUB activity. Further, USP37 deubiquitinates and stabilizes ERK1/2, thereby enhancing cancer cell proliferation. Thus, CDK2 is able to promote cell proliferation by activating USP37 and, in turn, stabilizing ERK1/2. Importantly, combined CDK1/2 and EGFR inhibitors have a synergetic anticancer effect through the downregulation of ERK1/2 stability and activity. Indeed, our patient-derived xenograft (PDX) results suggest that targeting both ERK1/2 stability and activity kills cancer cells more efficiently even at lower doses of these two inhibitors, which may reduce their associated side effects and indicate a potential new combination strategy for cancer therapy.
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