Integration of JAK/STAT receptor-ligand trafficking, signalling and gene expression in Drosophila melanogaster cells

Abstract

The JAK/STAT pathway is an essential signalling cascade required for multiple processes during development and for adult homeostasis. A key question in understanding this pathway is how it is regulated in different cell contexts. Here we have examined how endocytic processing contributes to signalling by the single cytokine receptor, Domeless, in Drosophila melanogaster cells. We identify an evolutionarily conserved di-Leu motif that is required for Domeless internalisation and show that endocytosis is required for activation of a subset of Domeless targets. Our data indicate that endocytosis both qualitatively and quantitatively regulates Domeless signalling. STAT92E, the single STAT transcription factor in Drosophila, appears to be the target of endocytic regulation and our studies show that phosphorylation of STAT92E on Tyr704, while necessary, is not always sufficient for target transcription. Finally, we identify a conserved residue, Thr702, which is essential for Tyr704 phosphorylation. Taken together, our findings identify previously unknown aspects of JAK/STAT pathway regulation likely to play key roles in the spatial and temporal regulation of signalling in vivo.

ClC‐c regulates the proliferation of intestinal stem cells via the EGFR signalling pathway in Drosophila

“…Previous studies have shown that blocking trafficking in distinct endosomal compartments leads to an inhibition of the JAK/STAT pathway, 56 and the internalization and endocytic trafficking of activated Dome allows for compartmentalized signalling to regulate subsets of Drosophila JAK/STAT transcriptional targets. 57 These results strongly supports that the internalization and trafficking are both required for JAK/STAT activity. Therefore, endocytosis may also affect the EGFR signalling pathway through indirect means.…”

Interferon Receptor Trafficking and Signaling: Journey to the Cross Roads

“…The essential role of CME in JAK/STAT signaling was further confirmed a year later in Drosophila with the receptor Domeless (Dome) whose internalization is also required to transduce JAK/STAT signaling, (105). Like IFNAR1 and IFNAR2, Dome presents fibronectin type-III extracellular domains (106) and a conserved di-leucine motif in its cytosolic tail (107). These data emphasize that the control of JAK/STAT signaling by receptor endocytosis is a conserved mechanism among species.…”

Systematic genome-scale identification of host factors for SARS-CoV-2 infection across models yields a core single gene dependency; ACE2

“…Many viruses are known to hijack endocytic mechanisms for entry to the cell (Robinson et al, 2018). However, an antiviral role could be the result of two scenarios: trafficking viral proteins to the lysosome for degradation (Park and Guo, 2014), or regulation of signalling pathways following activation by endocytosis of cytokine receptors (Moore et al, 2020; Zanin et al, 2020).…”