of the pathway, activation of receptors by their cognate ligands results in activation of Jaks which then transphosphorylate themselves and subsequently their substrates. Jak kinases contain seven JH (Jak/Janus homology) domains of which JH1 is the catalytic domain whereas JH2 is a pseudo-kinase domain with an autoregulatory function. Their presence accounts for the name of the two-faced Roman god Janus. Jh4 to Jh7 comprise the FERM domain important for the association with cytokine receptors. Activated Jaks phosphoporylate tyrosine residues on the cytoplasmic domain of the receptor which then serve as docking sites for the recrutiment of Stats to the receptor-Jak complex via the SH2 (src homology 2) domain of Stats. Jak phosphorylation of Stats is followed by Stat dimerization and translocation to the nucleus where they regulate the expression of specific target genes. The seven Stat transcription factors positively and negatively regulate the expression of a vast array of genes whose identification is still far from being complete. The combination of Stats and the tissue in which they act at a particular point of time, will dictate the subset of genes they control further contributing to the challenge of target identification. Constitutive phosphorylation of Stat1, Stat3 and Stat5 has been observed in several cancer lines and activating mutations for the Jak kinases of Stats have been reported. Various receptors may utilize particular Jak -Stat combinations. In the cytoplasm, the action of Jak-Stat is opposed by Socs family members, some of which represent a feedback inhibitory loop as their expression is under the control of Stat. Of note is the fact that Socs proteins negatively regulate both leptin and insulin signaling pathways. Several tyrosine phosphatases are also implicated in inhibiting the Jak-Stat pathway. In the nucleus, the action of Jak-Stat is opposed by members of the Pias family of proteins. Despite a good understanding of the overall scheme of the pathway, the details of individual receptor/Jak-Stat pathways, the evolution of the various Jak-Stat pathway 'isoforms', the mechanism and regulation of their actions are issues that remain to be elucidated. The diagram depicts a generic Jak-Stat signaling pathway. To see the ontology report for annotations, GViewer and download, click here
[click to see associated GO term - GO:0007259 and KEGG map - map04630]

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