The Janus Kinase (JAK) and signal transducers and activators of transcription (STAT) pathway has been shown to play a key role in cytokine-mediated signal transduction, and to regulate growth, differentiation, and death of both normal and transformed cells.
The JAK/STAT pathway represents one such signaling cascade whose evolutionarily conserved roles include cell proliferation and haematopoiesis. Jak belongs to a family of non-receptor protein tyrosine kinase of approximately 130kDa, comprising of Jak1, Jak2, Jak3 and Tyk2.
JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs. STATs are latent transcription factors that reside in the cytoplasm until activated. The seven mammalian STATs bear a conserved tyrosine residue near the C-terminus that is phosphorylated by JAKs. This phosphotyrosine permits the dimerization of STATs through interaction with a conserved SH2 domain. Phosphorylated STATs enter the nucleus by a mechanism that is dependent on importin -5 (also called nucleoprotein interactor 1) and the Ran nuclear import pathway.
Once in the nucleus, STAT dimers bind specific enhancers, regulating the transcription of target genes. In addition to activating STATs, Jak kinases phosphorylate other signaling/adaptor proteins, linking Jak signaling to other pathways such as the MAP kinases. These parallel regulatory pathways are important in shaping the specificity of cellular responses to various cytokines.
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