The combined action of the intracellular regions regulates FGFR2 kinase activity

Autor: Chi-Chuan Lin, Lukasz Wieteska, Guillaume Poncet-Montange, Kin Man Suen, Stefan T. Arold, Zamal Ahmed, John E. Ladbury
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Communications Biology, Vol 6, Iss 1, Pp 1-14 (2023)
Druh dokumentu: article
ISSN: 2399-3642
DOI: 10.1038/s42003-023-05112-6
Popis: Abstract Receptor tyrosine kinases (RTKs) are typically activated through a precise sequence of intracellular phosphorylation events starting with a tyrosine residue on the activation loop (A-loop) of the kinase domain (KD). From this point the mono-phosphorylated enzyme is active, but subject to stringent regulatory mechanisms which can vary dramatically across the different RTKs. In the absence of extracellular stimulation, fibroblast growth factor receptor 2 (FGFR2) exists in the mono-phosphorylated state in which catalytic activity is regulated to allow rapid response upon ligand binding, whilst restricting ligand-independent activation. Failure of this regulation is responsible for pathologic outcomes including cancer. Here we reveal the molecular mechanistic detail of KD control based on combinatorial interactions of the juxtamembrane (JM) and the C-terminal tail (CT) regions of the receptor. JM stabilizes the asymmetric dimeric KD required for substrate phosphorylation, whilst CT binding opposes dimerization, and down-regulates activity. Direct binding between JM and CT delays the recruitment of downstream effector proteins adding a further control step as the receptor proceeds to full activation. Our findings underscore the diversity in mechanisms of RTK oligomerisation and activation.
Databáze: Directory of Open Access Journals
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