Figure 1. The JAK-STAT signaling pathway in Drosophila melanogaster. (A) Activation of JAK-STAT signaling. Binding of either cytokine, Unpaired (Upd1, 2, and 3), to the type I cytokine receptor Domeless activates trans-phosphorylation of the JAK kinase Hopscotch (Hop) and Dome phosphorylation, creating a docking site for STAT (Stat92E). Hop-phosphorylated STAT forms dimers which translocate into the nucleus and activate target genes via binding to TTCN(3–4)GAA sites. The green box in Dome corresponds to the cytokine binding domain (CBM), the blue box to a conserved region between Lat/Et and Dome (LDHR), the fibronectin III (Fn III) motifs are in red, the signal peptide in yellow and the intra-cytoplasmic region in gray. (B) Negative regulation of JAK-STAT signaling. Lat/Et acts as a dominant negative Dome co-receptor. Suppressor of cytokine signaling (SOCS) (Socs36E, Socs44A) prevents Stat92E recruitment onto the receptor. Protein inhibitors of activated STAT (PIAS) and PTP61F inhibit Stat92E function. Sumoylation of Stat92E has a repressive role in the regulation of the JAK-STAT pathway in Drosophila. BCL6 (Ken and Barbie, marked Ken) and NURF compete with Stat92E for binding to DNA.