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- W4385582521 abstract "Abstract MET is a receptor tyrosine kinase (RTK) responsible for initiating signaling pathways involved in development and wound repair. MET activation relies on ligand binding to the extracellular receptor, which prompts dimerization, intracellular phosphorylation, and recruitment of associated signaling proteins. Mutations, which are predominantly observed clinically in the intracellular juxtamembrane and kinase domains, can disrupt typical MET regulatory mechanisms. Understanding how juxtamembrane variants, such as exon 14 skipping (METΔEx14), and rare kinase domain mutations can increase signaling, often leading to cancer, remains a challenge. Here, we perform a parallel deep mutational scan (DMS) of MET intracellular kinase domain in two fusion protein backgrounds: wild type and METΔEx14. Our comparative approach has revealed a critical hydrophobic interaction between a juxtamembrane segment and the kinase ⍺C helix, pointing to differences in regulatory mechanisms between MET and other RTKs. Additionally, we have uncovered a β5 motif that acts as a structural pivot for kinase domain activation in MET and other TAM family of kinases. We also describe a number of previously unknown activating mutations, aiding the effort to annotate driver, passenger, and drug resistance mutations in the MET kinase domain." @default.
- W4385582521 created "2023-08-05" @default.
- W4385582521 creator A5013884374 @default.
- W4385582521 creator A5026237036 @default.
- W4385582521 creator A5035793503 @default.
- W4385582521 creator A5041133975 @default.
- W4385582521 creator A5051355898 @default.
- W4385582521 creator A5052021235 @default.
- W4385582521 creator A5064513302 @default.
- W4385582521 creator A5080561155 @default.
- W4385582521 creator A5081018463 @default.
- W4385582521 date "2023-08-03" @default.
- W4385582521 modified "2023-10-03" @default.
- W4385582521 title "Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain" @default.
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