The Drosophila JAK-STAT pathway (original) (raw)

The molecular characterization of the JAK-STAT pathway has recently celebrated its 20th birthday, a milestone that marks the discovery of the tyrosine kinases TYK2 and JAK1 and the STAT1 and STAT2 transcription factors as the key factors underlying the cellular response to type I interferons. The initial description of the first JAK-STAT pathway components sparked a flurry of activity in multiple labs, which rapidly characterized a wide range of ligands, receptors, four JAKs, and seven STATs present in vertebrate cells. Collectively these factors signal through fundamentally similar mechanisms; a JAK-STAT pathway that now serves as a textbook example of how extracellular ligands can act at the cell surface to modulate nuclear gene expression. Hopscotch-the fly JAK. In contrast to the key role played by the Drosophila system in identifying many other key cellular signaling cascades, the initial steps leading to the identification of the Drosophila JAK-STAT pathway components lagged pioneering work being undertaken in vertebrate cell-based systems. However, the ball was set rolling in 1994 when the Perrimon lab cloned a novel gene termed Hopscotch (Hop), which encodes a maternally supplied protein required for the patterning of the embryonic cuticle (for an example of the LOF phenotype see ) and the proliferation of diploid imaginal cells. 5,6 Cloning of Hop identified it as a 1177 amino acid non-receptor tyrosine kinase, expressed throughout development, with a kinase domain, sharing 39% identity with JAK1, JAK2, and Tyk2, and an overall identity of 27% to JAK2. While not necessarily apparent at the time, the identification of JAK and the characteristic segmentation phenotype associated with pathway mutants represented a key insight and the first step on the path toward identifying the rest of the pathway.