激酶
磷酸化
基因
蛋白激酶A
体细胞
MAPK/ERK通路
突变体
地图2K7
生物
丝裂原活化蛋白激酶激酶
细胞周期蛋白依赖激酶2
化学
癌症研究
分子生物学
生物化学
作者
Emiko Kinoshita–Kikuta,Eiji Kinoshita,Sayaka Ueda,Yoko Ino,Yayoi Kimura,Hisashi Hirano,Takao Koike
标识
DOI:10.1016/j.bbapap.2018.05.004
摘要
The kinase MEK1 is an essential component of the mitogen-activated protein kinase cascades. Somatic mutations that have been identified in the MEK1-coding gene generally enhance kinase activity. Consequently, MEK1 has attracted much interest as a target for cancer therapy to block the aberrant activity. By using Phos-tag affinity electrophoresis, we found that the introduction of mutations detected in certain sporadic cancers or in MEK-inhibitor-resistant cancer cells produced constitutively active MEK1 species containing phosphorylated Ser-218 and Ser-222 residues; it also enhanced the constitutive activity of the kinase. Phosphorylation profiling of the mutants in the presence of inhibitors of RAF/MEK demonstrated that several mutations conferred resistance to multiple inhibitors as a result of an increase in the quantity of active MEK1 species containing the two phosphorylated Ser-218 and Ser-222 residues. Phos-tag-based phosphorylation profiling of MEK1 can therefore provide clinical insights into characteristics of individual mutations in the MEK1-coding gene.
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