ArticleCell reports2013
Cracking the molecular origin of intrinsic tyrosine kinase activity through analysis of pathogenic gain-of-function mutations.
Article in Cell reports, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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Who cites it
24 citing papers in PubMed, 55 citations in OpenAlex.
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- Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation.Nature chemical biology · 2020Article
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- A Conserved Allosteric Pathway in Tyrosine Kinase Regulation.Structure (London, England : 1993) · 2019Article
- Structure, activation and dysregulation of fibroblast growth factor receptor kinases: perspectives for clinical targeting.Biochemical Society transactions · 2018Review
- FGFR2 mutations are associated with poor outcomes in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study.Gynecologic oncology · 2017Article
- Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases.eLife · 2017Article
- Effects of FGFR2 kinase activation loop dynamics on catalytic activity.PLoS computational biology · 2017Article
- Conformational transition of FGFR kinase activation revealed by site-specific unnatural amino acid reporter and single molecule FRET.Scientific reports · 2017Article
- KinView: a visual comparative sequence analysis tool for integrated kinome research.Molecular bioSystems · 2016Article
- Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use.Oncotarget · 2016Article
- Two FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase Cγ.Molecular cell · 2016Article
- Ubiquitination switches EphA2 vesicular traffic from a continuous safeguard to a finite signalling mode.Nature communications · 2015Article
- DFG-out mode of inhibition by an irreversible type-1 inhibitor capable of overcoming gate-keeper mutations in FGF receptors.ACS chemical biology · 2015Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
The basal (ligand-independent) kinase activity of receptor tyrosine kinases (RTKs) promotes trans-phosphorylation on activation loop tyrosines upon ligand-induced receptor dimerization, thus upregulating intrinsic kinase activity and triggering intracellular signaling. To understand the molecular determinants of intrinsic kinase activity, we used X-ray crystallography and NMR spectroscopy to analyze pathogenic FGF receptor mutants with gradations in gain-of-function activity. These structural analyses revealed a "two-state" dynamic equilibrium model whereby the kinase toggles between an "inhibited," structurally rigid ground state and a more dynamic and heterogeneous active state. The pathogenic mutations have different abilities to shift this equilibrium toward the active state. The increase in the fractional population of FGF receptors in the active state correlates with the degree of gain-of-function activity and clinical severity. Our data demonstrate that the fractional population of RTKs in the active state determines intrinsic kinase activity and underscore how a slight increase in the active population of kinases can have grave consequences for human health.
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