Increase in constitutively active MEK1 species by introduction of MEK1 mutations identified in cancers

Publication date: Available online 9 May 2018Source: Biochimica et Biophysica Acta (BBA) - Proteins and ProteomicsAuthor(s): Emiko Kinoshita-Kikuta, Eiji Kinoshita, Sayaka Ueda, Yoko Ino, Yayoi Kimura, Hisashi Hirano, Tohru KoikeAbstractThe 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.

Source: Biochimica et Biophysica Acta (BBA) Proteins and Proteomics - July 5, 2018 Category: Biochemistry Source Type: research