Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations

Science. 2020 Feb 7;367(6478):643-652. doi: 10.1126/science.aaw3242.

Abstract

Homodimeric class I cytokine receptors are assumed to exist as preformed dimers that are activated by ligand-induced conformational changes. We quantified the dimerization of three prototypic class I cytokine receptors in the plasma membrane of living cells by single-molecule fluorescence microscopy. Spatial and spatiotemporal correlation of individual receptor subunits showed ligand-induced dimerization and revealed that the associated Janus kinase 2 (JAK2) dimerizes through its pseudokinase domain. Oncogenic receptor and hyperactive JAK2 mutants promoted ligand-independent dimerization, highlighting the formation of receptor dimers as the switch responsible for signal activation. Atomistic modeling and molecular dynamics simulations based on a detailed energetic analysis of the interactions involved in dimerization yielded a mechanistic blueprint for homodimeric class I cytokine receptor activation and its dysregulation by individual mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics
  • Carcinogenesis / genetics*
  • Cell Membrane / chemistry*
  • HeLa Cells
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / chemistry*
  • Janus Kinase 2 / genetics*
  • Ligands
  • Microscopy, Fluorescence
  • Models, Molecular
  • Mutation
  • Nitriles
  • Phenylalanine / genetics
  • Protein Multimerization*
  • Pyrazoles / pharmacology
  • Pyrimidines
  • Receptors, Erythropoietin / chemistry*
  • Receptors, Somatotropin / chemistry*
  • Receptors, Thrombopoietin / chemistry*
  • Signal Transduction
  • Single Molecule Imaging
  • Valine / genetics

Substances

  • Ligands
  • Nitriles
  • Pyrazoles
  • Pyrimidines
  • Receptors, Erythropoietin
  • Receptors, Somatotropin
  • Receptors, Thrombopoietin
  • Phenylalanine
  • ruxolitinib
  • Janus Kinase 2
  • Valine