- JAK-STAT signaling pathway
The JAK-STAT signaling pathway takes part in the regulation of cellular responses to
cytokine s andgrowth factor s. EmployingJanus kinase s (JAKs) and Signal Transducers and Activators of Transcription (STATs), the pathway transduces the signal carried by theseextracellular polypeptide s to thecell nucleus , where activatedSTAT protein s modifygene expression . Although STATs were originally discovered as targets ofJanus kinase s, it has now become apparent that certain stimuli can activate them independently of JAKs. The pathway plays a central role in principal cell fate decisions, regulating the processes ofcell proliferation , differentiation andapoptosis . It is particularly important inhematopoiesis - production ofblood cell s.Mechanism
JAKs, which have
tyrosine kinase activity, bind to some cell surfacecytokine receptors . The binding of the ligand to the receptor triggers activation of JAKs. With increased kinase activity, they form phosphorylatetyrosine residues on the receptor and create sites for interaction with proteins that containphosphotyrosine -bindingSH2 domain . STATs possessing SH2 domains capable of binding these phosphotyrosine residues are recruited to the receptors, and are themselves tyrosine-phosphorylated by JAKs. These phosphotyrosines then act as docking sites forSH2 domain s of other STATs, mediating their dimerisation. Different STATs form hetero- as well ashomodimer s. Activated STAT dimers accumulate in thecell nucleus and activate transcription of their target genes.cite online journal| author=Hebenstreit D, Horejs-Hoeck J and Duschl A | title=JAK/STAT-dependent gene regulation by cytokines | year=2005 | journal=Drug News Perspect | volume=18 | issue=4 | pages=243-249 | id=16034480] STATs may also be tyrosine-phosphorylated directly byreceptor tyrosine kinase s, such as theepidermal growth factor receptor as well as by non-receptortyrosine kinase s, such as c-src.The pathway is negatively regulated on multiple levels.
Protein tyrosine phosphatase s remove phosphates from cytokine receptors as well as activated STATs. More recently identified Suppressors of Cytokine Signaling (SOCS) inhibit STAT phosphorylation by binding and inhibiting JAKs or competing with STATs for phosphotyrosine binding sites on cytokine receptors.D. L. Krebs and D. J. Hilton. (2001) "SOCS proteins: negative regulators of cytokine signaling" in "Stem Cells" Volume 19, pages 378-387. Entrez Pubmed|11553846] STATs are also negatively regulated by Protein Inhibitors of Activated STATs (PIAS), which act in the nucleus through several mechanisms. [cite online journal| author=Shuai K | year=2006 | title=Regulation of cytokine signaling pathways by PIAS proteins | volume=16 | issue=2 | pages=196-202 | id=16474434] For example, PIAS1 and PIAS3 inhibit transcriptional activation by STAT1 and STAT3 respectively by binding and blocking access to the DNA sequences they recognise.References
Further reading
*Schroder, K., P. J. Hertzog, T. Ravasi & D. A. Hume (2004) "Interferon-γ: an overview of signals, mechanisms and functions". "Journal of Leukocyte Biology" 75:163-189.
*O'Shea, J. J., M. Gadina & R. D. Schreiber (2002) "Cytokine Signaling in 2002: New Surprises in the Jak/Stat Pathway". "Cell" 109, S121-S131.
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