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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Janus kinases promote cell-surface expression and provoke autonomous signalling from routing-defective G-CSF

Annemarie Meenhuis1, Mahban Irandoust, Albert Wölfler

  • 1Department of Hematology, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.

The Biochemical Journal
|October 17, 2008
PubMed

Insights

Janus kinases (JAKs) enhance granulocyte colony-stimulating factor receptor (CSF3R) stability and cell-surface expression in hematopoietic cells. This mechanism, acting in the endoplasmic reticulum, promotes cell survival and proliferation.

Area of Science:

  • Hematopoiesis
  • Cell signaling
  • Molecular biology

Background:

  • Granulocyte colony-stimulating factor receptor (CSF3R) signaling is crucial for myeloid cell development.
  • Janus kinases (JAKs) are key mediators of CSF3R signaling and are implicated in cytokine receptor expression.
  • JAKs may regulate receptor trafficking, influencing cell surface expression and downstream signaling.

Purpose of the Study:

  • To investigate the role of JAKs (JAK1, JAK2, TYK2) in regulating CSF3R cell-surface expression and stability.
  • To determine the mechanism by which JAKs affect CSF3R trafficking and function.
  • To explore the synergistic effects of increased JAK levels and CSF3R mutations on cell transformation.

Main Methods:

  • Quantification of cell-surface CSF3R expression in hematopoietic cells with varying JAK levels.
  • Analysis of CSF3R endocytosis and lysosomal degradation pathways.
  • Assessment of STAT3 activation and cell survival in response to CSF3R signaling.

Main Results:

  • Increased levels of JAK1, JAK2, and TYK2 elevated CSF3R cell-surface expression and protein stability.
  • JAKs did not inhibit CSF3R endocytosis or lysosomal degradation, suggesting an effect on biosynthesis.
  • JAKs acted on CSF3R within the endoplasmic reticulum.
  • Elevated JAK levels synergized with CSF3R mutants to promote growth-factor independent STAT3 activation and cell survival.

Conclusions:

  • JAKs enhance CSF3R stability and cell-surface expression by acting on the receptor in the endoplasmic reticulum.
  • This stabilization mechanism contributes to cell survival and proliferation.
  • Increased JAK expression coupled with impaired CSF3R trafficking provides a model for hematopoietic cell transformation.

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