The Jak-STAT pathway

doi:10.1016/S0161-5890(00)00018-3

Molecular Immunology

Volume 37, Issues 1–2, 1 January 2000, Pages 1-11

https://doi.org/10.1016/S0161-5890(00)00018-3 Get rights and content

Abstract

A variety of important cellular functions are regulated by cytokines. The Jak-STAT pathway is one of the important signaling pathways downstream of cytokine receptors. Following binding of a ligand to its cognate receptor, receptor-associated Jaks are activated. STAT proteins are then in turn activated by tyrosine phosphorylation by Jak kinases, allowing their dimerization and subsequent translocation into the nucleus, where they modulate expression of target genes. Indispensable functions of Jaks and STATs in cytokine signaling in vivo have been revealed through knockout mouse studies. Moreover, the recent discovery of the CIS/SOCS/JAB/SSI family of inhibitors has contributed to understanding how this pathway is negatively regulated.

Introduction

Cytokines control a variety of important biological responses related to hematopoiesis and immune function, including those related to cell growth, differentiation and anti-apoptotic signals (Leonard, 1999). Over the years, the signaling pathways induced by these cytokines have been extensively studied. One of the important pathways is that involving Janus family tyrosine kinases (Jak kinases) and signal transducers and activators of transcription (STAT proteins). Following binding of a ligand to its cognate receptor, receptor-associated Jaks and STATs are activated successively, leading to a rapid signaling from the cell surface to the nucleus (Ihle, 1995, Ihle, 1996, Leonard, 1996b, Darnell, 1997, O’Shea, 1997, Leonard and O’Shea, 1998). Gene targeting studies have confirmed the essential role played by the Jak-STAT pathway in driving biological responses to cytokines. In this review, we will discuss the importance of the Jak-STAT pathway, focusing on studies using knockout mice.

Section snippets

The Janus family tyrosine kinases

In mammals, four Jaks (Jak1, Jak2, Jak3 and Tyk2) have been identified (Horvath and Darnell, 1997, Leonard and O’Shea, 1998). Initially, the important function of Jak kinases in cytokine signaling was shown using mutagenized cell lines that lacked biological responsiveness to interferons (IFNs). Jak1-deficient or Tyk2-deficient cells were shown to be unresponsive to IFNα/β (Velazquez et al., 1992, Müller et al., 1993), whereas Jak1- or Jak2-deficient cells were found to have no response to IFNγ

Jak3 and severe combined immunodeficiency

It has been demonstrated that mutations in the common cytokine receptor γ chain (γ_c), which is shared by the receptors for IL-2, IL-4, IL-7, IL-9 and IL-15 (reviewed in Leonard, 1999), cause X-linked severe combined immunodeficiency (X-SCID) in humans (Noguchi et al., 1993a, Leonard, 1996a). Given that Jak3 specifically associates with γ_c, it was hypothesized that mutation of Jak3 might cause the similar phenotype (Russell et al., 1994). Indeed, patients with SCID due to mutations in Jak3 were

Mice deficient in Jak1 and Jak2

The phenotypes of Jak1-deficient (Rodig et al., 1998) and Jak2-deficient (Neubauer et al., 1998, Parganas et al., 1998) mice have been analyzed. Jak1 deficient mice show perinatal lethality, but lack other gross abnormalities. They are small at birth and fail to nurse. Lymphopoiesis but not myelopoiesis is severely impaired. Jak1-deficient cells fail to respond to cytokines that bind to three distinct families of cytokines, including interferons (type II cytokines), γ_c-dependent cytokines

The STAT gene family

Seven STAT proteins have been identified in mammalian cells (Leonard and O’Shea, 1998). The STATs are localized as clusters on chromosomes: Stat1 and Stat4 on chromosome 1, Stat2 and Stat6 on chromosome 10, and Stat3, Stat5a and Stat5b on chromosome 11 in murine system (Copeland et al., 1995). Stat5a and Stat5b have also been shown to colocalize on human chromosome 17 (Lin et al., 1996). This organization suggests that the genes arose through duplication of a common ancestral gene.

Structure of STATs

As shown in Fig. 3, all STATs share certain functional domains. Among them, the SH2 domain plays an important role in association between STATs and the receptors. Differences in the SH2 domains of different STATs determines the selectivity of STAT binding to various cytokine receptors. A conserved tyrosine approximately 700 residues from the N-terminus is rapidly phosphorylated by activated Jaks, allowing STAT proteins to then form dimers, based on the interaction between the SH2 domain of each

Interactions with other transcription factors

STATs have been found to associate with coactivator proteins. Stat1 has been shown to interact with Sp1 (Look et al., 1995). Stat3β has been shown to associate with c-Jun (Shaefer et al., 1995). The glucocorticoid receptor has been found to interact with Stat3, Stat5a and Stat5b (Zhang et al., 1997, Stocklin et al., 1996, Cella et al., 1998). The potent transcriptional activators CBP and p300 can interact with Stat1, Stat2, Stat5a, Stat5b and Stat6 at the carboxy terminal region of STATs (Zhang

STAT-deficient mice

So far all STATs genes except Stat2 have been gene-targeted in mice to elucidate the in vivo function of these proteins. The phenotypes of these mice reveal distinctive functions for the various STATs as shown in the following sections.

STATs in transformation

STAT activation has been found to be associated with viral or oncogene-mediated transformation. Stat3 is constitutively activated in transformed cells by Src tyrosine kinase (Yu et al., 1995), and recent data has supported the idea that Stat3 can function as an oncogene (Bromberg et al., 1999), and constitutive activation of STATs has been observed in cells transformed by viruses such as HTLV-I (Migone et al., 1995, Takemoto et al., 1997), v-Abl (Danial et al., 1995) and Epstein-Barr virus (

Negative regulation of Jak-Stat pathway

Degradation of STATs is one way by which the Jak-STAT pathway can be negatively regulated. Indeed, Stat1 has been shown to be a target of ubiquitin/proteasome-mediated degradation (Kim and Maniatis, 1996). Some STATs are found to have multiple forms by alternative splicing and degradation. Stat1 and Stat3 have truncated forms that lack C-terminal region by alternative splicing, and these forms are thought to act as a dominant negative one (Caldenhoven et al., 1996). Stat5 also has a truncated

Conclusions

As one of the main pathways downstream of cytokine receptors, the Jak-STAT signaling pathway has been intensively studied as a rapid membrane to nuclear signaling pathway. Moreover, a great deal of progress has been achieved in understanding how this pathway contributes to the specificity of cytokine signaling. The importance of STATs in cytokine-specific signaling has been shown in part through knockout mice studies, which indicate specific and indispensable functions of STATs in vivo.

Acknowledgements

We would like to thank Dr Panu Kovanen for his critical comments.

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¹: Present address: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharamachi, Sakyo-ku, Kyoto 606-8507, Japan

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Published by Elsevier Ltd.

ReviewThe Jak-STAT pathway

Abstract

Introduction

Section snippets

The Janus family tyrosine kinases

Jak3 and severe combined immunodeficiency

Mice deficient in Jak1 and Jak2

The STAT gene family

Structure of STATs

Interactions with other transcription factors

STAT-deficient mice

STATs in transformation

Negative regulation of Jak-Stat pathway

Conclusions

Acknowledgements

Cell

J. Biol. Chem.

Cell

Immunity

Cell

J. Biol. Chem.

Immunity

Genomics

Cell

Blood

Blood

Curr. Opin. Cell Biol.

Cell

Cell

Immunity

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

Cell

Biochem. Biophys. Res. Commun.

Blood

Cell

J. Biol. Chem.

Immunity

Immunity

Cell

J. Biol. Chem.

Cell

Immunity

Immunity

Cell

Immunity

Cell

J. Biol. Chem.

Immunity

Defective IL-2-mediated IL-2 receptor alpha chain expression in Stat3-deficient T lymphocytes

Int. Immunol.

Abrogation of bronchial eosinophilic inflammation and airway hyperreactivity in signal transducers and activators of transcription (STAT)6-deficient mice

J. Exp. Med.

Cooperation of Stat2 and p300/CBP in signalling induced by interferon α

Nature

Characterization of Stat5a and Stat5b homodimers and heterodimers and their association with the glucocorticoid receptor in mammary cells

Mol. Cell Biol.

Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients

J. Immunol.

Specific inhibition of Stat3 signal transduction by PIAS3

Science

Jak-STAT signaling induced by the v-abl oncogene

Science

Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins

Science

STATs and gene regulation

Science

Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins

Science

Lymphoid development in mice with a targeted deletion of the interleukin-2 receptor γ chain

Proc. Natl. Acad. Sci. USA

A new protein containing an SH2 domain that inhibits JAK kinases

Nature

Interaction of the growth hormone receptor cytoplasmic domain with the JAK2 tyrosine kinase

Endocrinology

Review
The Jak-STAT pathway