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  • Review Article
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Regulation of JAK–STAT signalling in the immune system

Key Points

  • The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway has a crucial role in the control of immune responses.

  • Abnormal JAK–STAT signalling is associated with immune disorders.

  • The JAK–STAT pathway is regulated at many steps by various proteins, including suppressor of cytokine signalling (SOCS) proteins, protein inhibitor of activated STAT (PIAS) proteins and protein tyrosine phosphatases.

  • SOCS and PIAS proteins inhibit JAK–STAT signalling through distinct mechanisms.

  • The activity of JAKs and STATs is regulated by various post-translational modifications, including phosphorylation, methylation, ubiquitylation and ISGylation. The cross-talk between the JAK–STAT pathway and other signalling pathways has an important role in regulating immune cells.

Abstract

The cytokine-activated Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway has an important role in the control of immune responses. Dysregulation of JAK–STAT signalling is associated with various immune disorders. The signalling strength, kinetics and specificity of the JAK–STAT pathway are modulated at many levels by distinct regulatory proteins. Here, we review recent studies on the regulation of the JAK–STAT pathway that will enhance our ability to design rational therapeutic strategies for immune diseases.

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Figure 1: The JAK–STAT pathway.
Figure 2: Negative regulation of the JAK–STAT pathway.
Figure 3: The SOCS family of proteins.
Figure 4: Proposed mechanisms for inhibiting the JAK–STAT pathway by PIAS proteins.
Figure 5: The cross-talk between cytokine-signalling pathways.

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Acknowledgements

This work is supported by the National Institutes of Health, American Cancer Society and United States Army Medical Research and Materiel Command (K.S.). B.L. is a Leukaemia and Lymphoma Special Fellow.

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Correspondence to Ke Shuai.

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DATABASES

LocusLink

BMP2

CAMK2

CD45

CIS

EPOR

JAK1

JAK2

JAK3

LEF1

LIF

PIAS1

PIAS3

PIASX

PIASY

PRMT1

PTP1B

SHP1

SHP2

SOCS1

SOCS2

SOCS3

STAT1

STAT2

STAT3

STAT4

STAT5A

STAT5B

STAT6

TC-PTP

TYK2

UBP43

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Glossary

LEPTIN

A hormone that regulates energy homeostasis and body weight. Leptin is mainly produced in white adipose tissue. Leptin binds to its receptor to signal through the JAK–STAT pathway.

NUCLEAR FACTOR-κB

(NF-κB). A family of transcription factors important for pro-inflammatory and anti-apoptotic responses. They are activated by the phosphorylation and subsequent ubiquitin-dependent proteolytic degradation of their respective inhibitors, known as inhibitor of κB (IκB). Phosphorylation of IκB occurs through tissue-specific kinases, IκB kinase 1 (IKK1) and IKK2.

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Shuai, K., Liu, B. Regulation of JAK–STAT signalling in the immune system. Nat Rev Immunol 3, 900–911 (2003). https://doi.org/10.1038/nri1226

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