Jak/STAT Signaling Pathway

The Jak/STAT pathway is a putative intracellular signaling pathway that mediates the effects of a large number of cytokines and growth factors. These compounds generally bind to receptors that lack intrinsic kinase activity and thus utilize intracellular enzymes to initiate downstream signaling. This signaling pathway is relatively straightforward as it includes only two main components: Janus Kinases (Jaks) and Signal Transducers and Activators of Transcription (STATs). Jak proteins are non-receptor tyrosine kinases that are constitutively associated with the cytoplasmic domain of receptors. The Jak family includes Jak1, Jak2, Jak3, and Tyk2 (Tyrosine Kinase 2). STAT proteins are latent transcription factors that reside in the cytoplasm until activated via phosphorylation, at which time they translocate to the nucleus. Seven STAT family members have thus far been identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.

The Jak/STAT pathway is activated following binding of a cytokine or growth factor to its respective receptor. Receptor engagement by a ligand initiates oligomerization of the receptor chains allowing the associated Jak proteins to activate each other by reciprocal tyrosine phosphorylation. The activated Jaks subsequently phosphorylate specific tyrosine residues in the intracellular domains of the receptor. These phosphorylated residues serve as docking sites for the Src homology 2 (SH2)-domain of STAT proteins. Once bound to the receptor, STAT proteins are phosphorylated by Jaks or other kinases, such as Src. Phosphorylated STATs dissociate from the receptor, dimerize, and then translocate to the nucleus where they complex with other nuclear proteins and bind to specific sequences to regulate the expression of target genes.

To date, over 50 cytokines and growth factors have been shown to utilize the four Jak proteins and seven STAT molecules to regulate cell growth, survival differentiation, motility, and immune responses. Activators of the Jak/STAT signaling pathway include type I/II Interferons, the IL-6, IL-10, IL-12, Common gamma Chain, and Common beta Chain families of cytokines, and numerous growth factors that signal through homodimeric hormone receptors, receptor tyrosine kinases, and G protein-coupled receptors. These receptors activate the same general Jak/STAT pathway, though several notable differences occur. STAT1 and STAT2 activated by type I Interferons associate with Interferon Regulatory Factor 9 (IRF9), also called ISGF3-gamma, to form an Interferon-Stimulated Gene Factor-3 (ISGF3) complex. This complex translocates to the nucleus and binds to the interferon-sensitive response element (ISRE). Additionally, Angiotensin II activates the Jak/STAT pathway by two mechanisms. It stimulates the association of Jak proteins, followed by their subsequent phosphorylation, to the Angiotensin II Receptor, Type 1 (AGTR-1) via the tyrosine phosphatase SHP-2. Angiotensin II also stimulates Jak phosphorylation by Proline-rich Tyrosine Kinase 2 (PYK2) via the PLC-IP3-Ca²⁺- and PLC-DAG-PKC-delta-mediated pathways.

This interactive pathway illustrates a comprehensive list of all Jak and STAT proteins reported to be activated by the different receptor families. It is generally accepted that receptors preferably signal through specific Jak and STAT proteins. However, several factors, such as expression profiles of Jak and STAT proteins, the presence of regulatory molecules, and crosstalk from other signaling pathways, can influence which Jak and STAT proteins are activated by a receptor. To view the references for this information, please visit our Jak/STAT reference table.

To learn more, please visit our Jak/STAT Signaling Research Area.