Signaling by STATs

Abstract

A variety of cytokines and growth factors use the Janus kinase (Jak)-STAT signaling pathway to transmit extracellular signals to the nucleus. STATs (signal transducers and activators of transcription) are latent cytoplasmic transcription factors. There are seven mammalian STATs and they have critical, nonredundant roles in mediating cellular transcriptional responses to cytokines. The physiological roles of STATs have been elucidated by analysis of mice rendered deficient in STAT genes. STAT activation is regulated and can be modulated in a positive or negative fashion; it can be reprogrammed to drive different cellular responses. Several auto-regulatory and signaling crosstalk mechanisms for regulating Jak-STAT signaling have been described. Understanding and manipulation of the function of STATs will help in the development of therapeutic strategies for diseases that are regulated by cytokines.

Figure 1

Cytokine activation of the Jak–STAT pathway. Cytokine ligation and dimerization of plasma membrane receptors results in activation of receptor-associated Jak kinases and phosphorylation of receptor cytoplasmic domain tyrosine residues. STATs dock on these phosphotyrosine motifs by means of their Src homology 2 (SH2) domains. STATs are then phosphorylated on a conserved carboxy-terminus tyrosine, dimerize, and translocate to the nucleus to activate gene transcription. Transcriptional responses can be detected within a few minutes of receptor ligation. The use of a small number of protein:protein or protein:DNA interactions between the extracellular ligand and gene promoters allows specificity in signal transduction. Jak, Janus kinase; STAT, signal transducer and activator of transcription.

Figure 2

Activation of positive and negative feedback loops by interferons (IFNs). Low priming doses of IFNs will preferentially activate positive feedback loops, such as association with other receptors (not shown) and the induction of expression of IFN-stimulated genes that function as positive regulators of signaling, such as STAT1 and interferon-stimulated gene 15 (ISG15) (right). Higher doses of IFNs will also activate feedback inhibition, such as the induction of expression of suppressors of cytokine signaling (SOCS) (left). Jak, Janus kinase; STAT, signal transducer and activator of transcription.