Janus kinases promote cell surface expression and provoke autonomous signalling from routing defective G-CSF receptors

Annemarie Meenhuis , Mahban Irandoust , Albert Wölfler , Onno Roovers , Marijke Valkhof , Ivo P Touw (1)

1 Erasmus MC - Erasmus University Medical Center [Rotterdam]

The G-CSF receptor (CSF3R) controls survival, proliferation and differentiation of myeloid progenitor cells via activation of multiple Janus kinases (JAKs). In addition to their role in phosphorylation of receptor tyrosines 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. Here we show that increasing the levels of JAK1, JAK2 and TYK2 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 nor lysine-mediated lysosomal degradation of CSF3R. Rather, JAKs appeared to act on CSF3R in the biosynthetic pathway at the level of the ER. Strikingly, increased JAK levels synergized with internalization or lysosomal routing defective CSF3R mutants to confer growth factor independent STAT3 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.

Mots clés: Life Sciences

Annemarie Meenhuis, Mahban Irandoust, Albert Wölfler, Onno Roovers, Marijke Valkhof, et al.. Janus kinases promote cell surface expression and provoke autonomous signalling from routing defective G-CSF receptors. Biochemical Journal, 2009, 417 (3), pp.737-746. ⟨10.1042/BJ20081153⟩. ⟨hal-00479040⟩