| Background |
Members of the Janus family of tyrosine kinases (Jak1, Jak2, Jak3, and Tyk2) are activated by ligands binding to a number of associated cytokine receptors Upon cytokine receptor activation, Jak proteins become autophosphorylated and phosphorylate their associated receptors to provide multiple binding sites for signaling proteins. These associated signaling proteins, such as Stats Shc insulin receptor substrates and focal adhesion kinase (FAK) typically contain SH2 or other phosphotyrosine-binding domains.Activation of Jak kinases upon cytokine receptor binding is associated with tyrosine phosphorylation within their activation loops, including Tyr1034/1035 of Jak1, Tyr1007/1008 of Jak2, Tyr980/981 of Jak3, and Tyr1054/1055 of Tyk2. Many studies have indicated that various cytokine receptors have clear preferences that utilize distinct Jak family members. Aberrant regulation of Jak signaling is associated with a number of diseases, including myeloproliferative neoplasms, leukemia, and inflammatory disease.
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