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Janus kinases promote cell-surface expression and provoke autonomous signalling from routing-defective G-CSF receptors.
- Source :
-
The Biochemical journal [Biochem J] 2009 Feb 01; Vol. 417 (3), pp. 737-46. - Publication Year :
- 2009
-
Abstract
- CSF3R [G-CSF (granulocyte colony-stimulating factor) receptor] controls survival, proliferation and differentiation of myeloid progenitor cells via activation of multiple JAKs (Janus kinases). In addition to their role in phosphorylation of receptor tyrosine residues and downstream signalling substrates, JAKs have recently been implicated in controlling expression of cytokine receptors, predominantly by masking critical motifs involved in endocytosis and lysosomal targeting. In the present study, we show that increasing the levels of JAK1, JAK2 and TYK2 (tyrosine kinase 2) elevated steady-state CSF3R cell-surface expression and enhanced CSF3R protein stability in haematopoietic cells. This effect was not due to inhibition of endocytotic routing, since JAKs did not functionally interfere with the dileucine-based internalization motif or lysine-mediated lysosomal degradation of CSF3R. Rather, JAKs appeared to act on CSF3R in the biosynthetic pathway at the level of the ER (endoplasmic reticulum). Strikingly, increased JAK levels synergized with internalization- or lysosomal-routing-defective CSF3R mutants to confer growth-factor independent STAT3 (signal transducer and activator of transcription 3) activation and cell survival, providing a model for how increased JAK expression and disturbed intracellular routing of CSF3R synergize in the transformation of haematopoietic cells.
- Subjects :
- Animals
Cell Line, Tumor
Endocytosis
HeLa Cells
Humans
Ligands
Lysosomes metabolism
Mice
Receptors, Colony-Stimulating Factor genetics
Receptors, Colony-Stimulating Factor metabolism
Receptors, Granulocyte Colony-Stimulating Factor genetics
Transfection
Ubiquitination
Cell Membrane metabolism
Janus Kinases metabolism
Receptors, Granulocyte Colony-Stimulating Factor metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8728
- Volume :
- 417
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Biochemical journal
- Publication Type :
- Academic Journal
- Accession number :
- 18922133
- Full Text :
- https://doi.org/10.1042/BJ20081153