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Updated: Dec 17, 2025

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JAK2 regulates Nav1.6 channel function via FGF14Y158 phosphorylation.

Paul A Wadsworth1, Aditya K Singh2, Nghi Nguyen3

  • 1Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology & Toxicology, The University of Texas Medical Branch, Galveston, TX, USA.

Biochimica Et Biophysica Acta. Molecular Cell Research
|June 30, 2020
PubMed
Summary

Janus kinase 2 (JAK2) regulates neuronal firing by controlling fibroblast growth factor 14 (FGF14) interactions with voltage-gated sodium channels. JAK2 inhibition alters FGF14 dimerization, impacting channel function and neuronal activity.

Keywords:
FGF14JAK2SignalingSodium channelsTyrosine kinases

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Protein interactions involving voltage-gated sodium (Nav) channels and accessory proteins are crucial for neuronal excitability and plasticity.
  • The repertoire of identified kinases regulating these Nav channel complexes remains limited.
  • Fibroblast growth factor 14 (FGF14) is an accessory protein essential for Nav channel function, possessing unexplored phosphorylation sites that may mediate kinase regulation.

Purpose of the Study:

  • To identify novel kinases that indirectly regulate Nav channels through modulation of FGF14.
  • To investigate the functional consequences of kinase activity on the FGF14:Nav1.6 complex and neuronal firing.

Main Methods:

  • Conducted an in-cell high-throughput screen (HTS) of over 3000 compounds targeting the FGF14:Nav1.6 complex.
  • Utilized in vitro phosphorylation assays, biophysics, mass spectrometry, and patch-clamp electrophysiology to analyze kinase regulation.
  • Employed the JAK2 inhibitor Fedratinib in hippocampal CA1 pyramidal neurons.

Main Results:

  • Compounds targeting Janus kinase 2 (JAK2) were significantly enriched among HTS hits.
  • Mass spectrometry identified FGF14Y158 as a JAK2 phosphorylation site, critical for FGF14 homodimerization and Nav1.6 interaction.
  • JAK2 inhibition increased FGF14 homodimerization inversely to FGF14:Nav1.6 complex formation, and Fedratinib reduced neuronal firing dependent on FGF14.

Conclusions:

  • Neuronal JAK2 levels directly influence neuronal firing and plasticity by modulating the FGF14 dimerization equilibrium.
  • This regulation impacts the availability of monomeric FGF14 for interaction with Nav1.6 channels, revealing a novel regulatory mechanism.