Abstract
Receptor tyrosine kinases (RTKs) are single-pass transmembrane receptors whose activation is tightly regulated by intra-domain interactions within both their extracellular and intracellular regions. The intracellular juxtamembrane (JM) domain, which links the transmembrane and kinase domains (KDs), often plays a critical role in modulating kinase activity. The MET receptor, activated by hepatocyte growth factor, requires precise regulation to support normal development and wound healing but becomes a potent oncogene when overexpressed or mutated. A common oncogenic lesion in MET, caused by exon 14 skipping, leads to partial deletion of its unusually long intracellular JM domain and is frequently detected in non-small cell lung cancer, as well as pancreatic, liver, and brain cancers. Despite its length and abundance of posttranslational modifications, the functional role of the MET JM domain has remained poorly understood. We have uncovered that this segment regulates the kinetics of MET kinase activation. Specifically, we found that a membrane-proximal, N-terminal region of the JM domain accelerates activation loop phosphorylation, promoting kinase transition to an active state. This regulation does not depend on the oligomeric state of MET but likely acts allosterically to enhance autophosphorylation of the KD. Notably, this function is absent from the closely related MST1R/RON RTK, suggesting it is a unique feature of the MET receptor. Together, these findings uncover a previously unrecognized layer of MET regulation with potential implications for the development of selective therapies targeting MET-driven cancers.