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Brown, S., Hu, N., Castelli-Gair Hombria, J. (2003). Novel level of signalling control in the JAK/STAT pathway revealed by in situ visualisation of protein-protein interaction during Drosophila development.  Development 130(14): 3077--3084.
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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 beta-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 rename betalue-betalau 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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