
MET 수용체 타이로신 키나제 도메인의 돌연변이 스캐닝을 통해 세포막 근처 도메인과 키나제 N-엽의 중요한 조절 메커니즘을 밝혀냈다.


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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 the 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 potential differences in regulatory mechanisms between MET and other RTKs. Additionally, we have uncovered a β5 motif that acts as a structural pivot for the kinase domain 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.

### Competing Interest Statement

JSF is a consultant for, has equity in, and receives research support from Relay Therapeutics. N.J. is a founder of Rezo Therapeutics and a shareholder of Rezo Therapeutics, Sudo Therapeutics, and Type6 Therapeutics. N.J. is a SAB member of Sudo Therapeutics, Type6 Therapeutic and NIBR Oncology. The Jura laboratory has received sponsored research support from Genentech, Rezo Therapeutics and Type6 Therapeutics. E.A.C. is a consultant at IHP Therapeutics, Valar Labs, Tatara Therapeutics and Pear Diagnostics, reports receiving commercial research grants from Pfizer, and has stock ownership in Tatara Therapeutics, HDT Bio, Clara Health, Aqtual, and Guardant Health.

Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain

met-수용체-타이로신-키나제-도메인에-대한-깊이-있는-돌연변이-스캐닝을-통해-밝혀진-세포막-근처-도메인과-키나제-n-엽의-보존된-조절-모티프


MET 수용체 타이로신 키나제 도메인에 대한 깊이 있는 돌연변이 스캐닝을 통해 밝혀진 세포막 근처 도메인과 키나제 N-엽의 보존된 조절 모티프
