Mutation in the Jak Kinase JH2 Domain Hyperactivates Drosophila and Mammalian Jak-Stat Pathways

Abstract

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.

The roles of the Drosophila JAK/STAT pathway

“…These substitutions represent the only hyper-activating mutations currently identi®ed in any JAK kinase. An equivalent substitution to the hop Tum-l allele engineered into murine JAK2 results in similar overactive molecules (Luo et al, 1997). hop Tum-l individuals form 5 ± 20-fold more plasmatocytes when raised above the restrictive temperature.…”

“…The hop Tum-l allele is a point mutation (G431E, see Figure 1b) of a residue otherwise unconserved in other JAKs (Hanratty and Dearolf, 1993). The other, hop T42 , is slightly stronger than hop Tum-l and also contains a single amino acid substitution (E695K, see Figure 1b) present in the kinase-like domain and represents the mutation of a residue conserved in all known JAK homologues (Luo et al, 1997). These substitutions represent the only hyper-activating mutations currently identi®ed in any JAK kinase.…”

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

“…The kinase-like JH2 domain, despite harboring most of the conserved amino acid residues characteristic of the kinase domain, lacks any observable tyrosine kinase activity. It is now clear that this kinase-like domain plays a regulatory role (Luo et al, 1997). The sequences that are amino terminal to the kinase and kinase-like domains bear no resemblance to any characterized protein motif.…”

JAK-STAT signaling activated by Abl oncogenes

“…A gain of function mutation in murine JAK 2, which was engineered to mimic that in the Drosophila tumorigenic allele of hopscotch, can activate STAT 5, but cannot bypass the requirement for cytokines in proliferation of factor dependent cells (Luo et al, 1997). On the other hand, the TEL/JAK 2 fusion protein can transform factor dependent cell lines or primary bone marrow cells, and can generate tumors in mice (Ho et al, 1999;Schwaller et al, 1998).…”