Novel level of signalling control in the JAK/STAT pathway revealed by in situ visualisation of protein-protein interaction during Drosophila development.
2003
It is commonly accepted that activation of most signalling pathways is
induced by ligand receptor dimerisation. This belief has been challenged for
some vertebrate cytokine receptors of the JAK/STAT pathway. Here we study
whether DOME, the Drosophila receptor of the JAK/STAT pathway, can
dimerise and if the dimerisation is ligand-dependent. To analyse DOME
homo-dimerisation, we have applied a β-gal complementation technique that
allows the detection of protein interactions in situ. This technique has been
used previously in cell culture but this is the first time that it has been
applied to whole embryos. We show that this technique, which we renameβ
lue-βlau technique, can be used to detect DOME homo-dimerisation in
Drosophila developing embryos. Despite DOME being ubiquitously
expressed, dimerisation is developmentally regulated. We investigate the state
of DOME dimerisation in the presence or absence of ligand and show that DOME
dimerisation is not ligand-induced, indicating that ligand independent
cytokine receptor dimerisation is a conserved feature across phyla. We have
further analysed the functional significance of ligand-independent receptor
dimerisation by comparing the effects of ectopic ligand expression in cells in
which the receptor is, or is not, dimerised. We show that ligand expression
can only activate STAT downstream targets or affect embryo development in
cells in which the receptor is dimerised. These results suggest a model in
which ligand-independent dimerisation of the JAK/STAT receptor confers cells
with competence to activate the pathway prior to ligand reception. Thus,
competence to induce the JAK/STAT signalling pathway in Drosophila
can be regulated by controlling receptor dimerisation prior to ligand binding.
These results reveal a novel level of JAK/STAT signalling regulation that
could also apply to vertebrates.
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