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Review
. 2015 Jan 1;194(1):21-7.
doi: 10.4049/jimmunol.1401867.

Mechanisms of Jak/STAT signaling in immunity and disease

Alejandro V Villarino  1 , Yuka Kanno  1 , John R Ferdinand  1 , John J O'Shea  2
Affiliations
Review

Mechanisms of Jak/STAT signaling in immunity and disease

Alejandro V Villarino et al. J Immunol. .

Abstract

More than two decades ago, experiments on the antiviral mechanisms of IFNs led to the discovery of JAKs and their downstream effectors, the STAT proteins. This pathway has since become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors, including cytokines and hormones, mediate their diverse functions. Jak/STAT research has not only impacted basic science, particularly in the context of intercellular communication and cell-extrinsic control of gene expression, it also has become a prototype for transition from bench to bedside, culminating in the development and clinical implementation of pathway-specific therapeutics. This brief review synthesizes our current understanding of Jak/STAT biology while taking stock of the lessons learned and the challenges that lie ahead.

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Figures

Figure 1
Figure 1
Canonical Jak/STAT signaling begins with the association of cytokines and their corresponding transmembrane receptors. This brings Jaks in proximity, leading to phosphorylation of both the Jaks themselves and the cytoplasmic tails of the receptors, creating requisite docking sites for latent STAT monomers. STAT tyrosine phosphorylation (p-Tyr) then proceeds as the major activating event, leading to dimerization, translocation, DNA binding and target gene induction. Non-canonical deviations from this model should also be considered. First, p-Tyr can occur via Jak-independent pathways and, in fact, is not required for some activities (unphosphorylated STATs). Additional post-translational modifications (e.g. serine phosphorylation) can also influence STATs. Next, although each cytokine/receptor is typically associated with a particular STAT, most engage more than one family member (heterogeneous signaling), leading to the formation of not only homodimers but also heterodimers and higher order tetramers. These migrate to the nucleus where they bind to DNA not only through consensus GAS elements, but also through GAS-independent mechanisms, leading to induction, repression or neutral binding of protein-coding (mRNAs) or non-coding (miRNAs and lncRNAs) target genes, typically as part of multi-molecular complexes. Due to a shared affinity for GAS motifs, multiple STATs may bind to the same target sites (overlapping specificities). They can also bind to and promote remodeling of gene enhancers and can regulate the epigenetic status of target genes. Lastly, extra-nuclear functions have increasingly been recognized, most notably in the mitochondrion.
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