Proteins of the Jak family of non‐receptor kinases play important roles in mammalian hematopoietic signal transduction. They mediate the cellular response to a wide range of cytokines and growth factors. A dominant mutation in a Drosophila Jak kinase, hopscotchTumorous‐lethal (hopTum‐l), causes hematopoietic defects. Here we conduct a molecular analysis of hopTum‐l. We demonstrate that the hopTum‐l hematopoietic phenotype is caused by a single amino acid substitution of glycine to glutamic acid at residue 341. We generate a true revertant of the hopTum‐l mutation, in which both the molecular lesion and the mutant hematopoietic phenotype revert back to wild type. We also examine the effects of the G341E substitution in transgenic flies. The results indicate that a mutant Jak kinase can cause leukemia‐like abnormalities.

The Jak (Janus) family of nonreceptor tyrosine kinases plays a critical role in cytokine signal transduction pathways. In Drosophila melanogaster, the dominant hop A major advance in understanding cytokine signal transduction pathways has come from recent studies on the Jak (Janus) family of nonreceptor tyrosine kinases (reviewed in references 18, 19, and 36). These proteins are structurally different from other cytoplasmic protein tyrosine kinases, as they contain a kinase-like (JH2) domain adjacent to the carboxy-terminal kinase (JH1) domain and lack src homology 2 (SH2) and SH3 domains. Jak kinases associate with the intracellular domains of a large number of cytokine and growth factor receptors, and their roles in intracellular signaling can generally be explained as follows. After the extracellular ligand binds to its receptor, the Jak kinases become rapidly phosphorylated on tyrosine. They then phosphorylate the receptor, which provides docking sites for latent cytoplasmic transcription factors termed Stat (for signal transducers and activators of transcription) proteins. The Jak kinases then phosphorylate the Stat proteins, which in turn dissociate from the receptor complex, form homodimers or heterodimers, and translocate to the nucleus.

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