A Reference Guide for Jak/STAT Signaling

The Jak/STAT pathway is one of the primary signaling pathways activated by cytokines and growth factors. It is activated by numerous compounds, and each ligand/receptor complex can activate multiple Jak and STAT proteins. To help sort out the complexity of Jak/STAT activation, a list of receptors and the Jak and STAT family members they activate have been assembled into a reference table.

The Jak/STAT Pathway

The Jak/STAT pathway mediates the effects of a large number of cytokines and growth factors. These proteins 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 typically 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.¹ Activators of the Jak/STAT 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 receptors, receptor tyrosine kinases, and G protein-coupled receptors. The different receptor classes that activate the Jak/STAT pathway display specificity for one Jak or Jak combination, though they appear to activate multiple STAT proteins.² Likewise, it does not appear that activated Jaks exhibit specificity for a particular STAT because different receptors activate a common STAT but distinctly different Jaks.³ It is generally accepted, though, 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.

The reference table below is a comprehensive index of ligands and receptors, and the Jak and STAT proteins they have been documented to activate. Explore this table to see which Jak and STAT proteins are activated by your receptor of interest.

Jump to a Section

• Type I/II Interferons
• Receptor Tyrosine Kinases
• Homodimeric Hormone Receptors
• Common beta Chain Receptor Family
• Common gamma Chain Receptor Family
• IL-6 Family
• IL-10 Family
• IL-12 Family
• G Protein-Coupled Receptors
• References

Type I/II Interferons

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Receptor Tyrosine Kinases

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Homodimeric Hormone Receptors

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Common beta Chain Receptor Family

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Common gamma Chain Receptor Family

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IL-6 Family

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IL-10 Family

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IL-12 Family

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G Protein-Coupled Receptors

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