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Real time characterization of the MAPK pathway using native mass spectrometry
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Journal Article
Real time characterization of the MAPK pathway using native mass spectrometry
2025
Overview
The MAPK pathway is a crucial cell-signaling cascade that is composed of RAS, MEK, BRAF, and ERK, which serves to connect extracellular signals to intracellular responses. Over-activating mutations in the MAPK pathway can lead to uncontrolled cell growth ultimately resulting in various types of cancer. While this pathway has been heavily studied using a battery of techniques, herein we employ native mass spectrometry (MS) to characterize the MAPK pathway, including nucleotide, drug, and protein interactions. We utilize native MS to provide detailed insights into nucleotide and drug binding to BRAF complexes, such as modulation of nucleotide binding in the presence of MEK1. We then demonstrate that different CRAF segments vary in their complex formation with KRAS, with the addition of the cysteine rich domain (CRD) enhancing complex formation compared to Ras binding domain (RBD) alone. We report differences in KRAS GTPase activity in the presence of different RAF segments, with KRAS exhibiting significantly enhanced nucleotide turnover when bound to CRAF fragments. We use ERK2 as a downstream readout to monitor the MAPK phosphorylation cascade. This study demonstrates the utility of native MS to provide detailed characterization of individual MAPK pathway components and monitor the phosphorylation cascade in real time.
Native mass spectrometry enables real time characterization of MAPK phosphorylation cascade and impact of oncogenic RAS mutants on kinetics.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
