Suppression of cytokine signaling: The SOCS perspective

doi:10.1016/j.cytogfr.2013.03.005

Cytokine & Growth Factor Reviews

Volume 24, Issue 3, June 2013, Pages 241-248

https://doi.org/10.1016/j.cytogfr.2013.03.005 Get rights and content

Abstract

The discovery of the Suppressor of Cytokine Signaling (SOCS) family of proteins has resulted in a significant body of research dedicated to dissecting their biological functions and the molecular mechanisms by which they achieve potent and specific inhibition of cytokine and growth factor signaling. The Australian contribution to this field has been substantial, with the initial discovery of SOCS1 by Hilton, Starr and colleagues (discovered concurrently by two other groups) and the following work, providing a new perspective on the regulation of JAK/STAT signaling. In this review, we reflect on the critical discoveries that have lead to our current understanding of how SOCS proteins function and discuss what we see as important questions for future research.

Section snippets

Preface

Cytokines are important soluble mediators of many physiological processes, including growth and development, and the innate and adaptive immune responses. Cytokine engagement with cognate cell surface receptors initiates intracellular signaling cascades, which culminate in changes to the transcriptional profile of the cell. These cascades are inextricably linked to the JAK protein tyrosine kinases and their substrates, the Signal Transducers and Activators of Transcription, or STAT proteins.

Biological role of the SOCS proteins

Early studies of the SOCS proteins showed that transcription of the Cis, Socs1, 2 and 3 genes was induced by many different cytokines and conversely, that forced expression of SOCS1 and SOCS3 could inhibit signaling from multiple receptor complexes. The specificity inherent in these biological systems began to emerge with the generation and analysis of genetically targeted mice, which lacked individual Socs genes.

Deletion of the Socs1 gene resulted in mice that died shortly after weaning due to

Biochemical mechanism of action

The SOCS proteins have been demonstrated to inhibit signaling through three primary mechanisms, all of which rely in part on their SH2 domains. CIS and SOCS2 have been proposed to act by competing with STAT proteins for binding to phosphorylated tyrosine residues within the receptor cytoplasmic domains, SOCS1 and SOCS3 directly inhibit JAK activity via an interaction that involves the SH2 domain and a short region preceding it, which is known as the kinase inhibitory region (KIR), and through

SOCS in disease: a case for therapeutic intervention?

Activating mutations in kinases and other components of intracellular signaling cascades are now inextricably linked to a variety of cancers. Given the role of JAK/STAT signaling in hemopoiesis and the immune system, it is perhaps not surprising that disruption of normal JAK activity has been shown in patients with acute lymphoblastic leukemia (ALL) and is particularly commonplace in myeloproliferative disease [67]. For example, mutation of Val617 to Phe in the pseudo-kinase domain of JAK2,

Concluding remarks

It is becoming increasingly clear that the SOCS proteins can interact independently of the canonical SH2-phosphotyrosine interactions; in particular the long N-termini of SOCS4–7 are predicted to mediate protein interactions [86]. Key questions remain for these lesser-studied family members, including whether they act to inhibit JAK/STAT signaling, or contribute to the negative regulation of other signaling cascades.

The SOCS protein family has been extensively studied in Australia, due in no

Acknowledgements

We thank Warren Alexander and Nick Nicola for critical reading of this manuscript. This work was supported in part by the National Health and Medical Research Council (NHMRC), Australia (Program Grant #487922), as well as an NHMRC IRIISS Grant 361646 and a Victorian State Government Operational Infrastructure Scheme grant. S.E.N. is supported by an NHMRC Fellowship, J.J.B. by an ARC Future Fellowship (FT110100169) and E.M.L. by an Australian Postgraduate Award. This work was also supported in

Edmond M. Linossi is a postgraduate student at the Walter and Eliza Hall Institute in the Inflammation Division. He graduated from the University of Melbourne in 2011 and was awarded an Australian Postgraduate Award. His current work aims to investigate the role of the lesser known SOCS4 and SOCS5.

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Jeffrey J. Babon, Laboratory Head at the Walter and Eliza Hall Institute of Medical Research (Australia). He was born in 1972 and is a specialist in the field of structural biology and biochemistry. He is a graduate of Melbourne University and obtained his PhD at the Murdoch Institute. Postdoctoral training: Jeff Babon undertook postdoctoral training at the National Institute of Medical Research (London, UK), 2000–2003, in the division of Molecular Structure and then returned to Australia in 2003 to take a postdoctoral position in the Structural Biology Division at the Walter and Eliza Hall Institute. Major research interest: The group of Dr. Babon focusses on the regulation of Cytokine Signaling, in particular the inhibition of JAK/STAT signaling via the SOCS (Suppressor of Cytokine Signaling) family of proteins. He uses structural biology and biochemistry to study mechanism within these pathways to understand the role they play in hematological disease.

Prof. Douglas J. Hilton PhD FAA FTSE, born in 1964, is the 6th Director of the Walter and Eliza Hall Institute (WEHI), Australia, Head of its division of Molecular Medicine and head of the Department of Medical Biology in the Faculty of Medicine, Dentistry and Health Sciences at the University of Melbourne. Postdoctoral training: 1991–1993, The Whitehead Institute, MIT in Cambridge working on the structure/function relationship of the erythropoietin receptor; 1993–1995, Cancer and Haematology Division, WEHI, Australia. Academic appointments: Hilton became a laboratory head at WEHI in 1996, was appointed Director of Cooperative Research Centre for Cellular Growth Factors (1997–2001), Head of Molecular Medicine Division at WEHI (since 2006), and since 2009 Professor and Head of Department of Medical Biology at the University of Melbourne, and Director of WEHI. Awards and honors: Hilton has received many prizes and awards for his research into how blood cells communicate, including the Amgen Medical Researcher Award, the inaugural Commonwealth Health Minister's Award for Excellence in Health and Medical Research, the GSK Australia Award for Research Excellence, Milstein Award from the International Society of Interferon and Cytokine Research, Lemberg Medal from the Australian Society of Biochemistry and Molecular Biology, was elected a Fellow of the Australian Academy of Science in 2004, and a Fellow of the Academy of Technological Sciences and Engineering in 2010. Major research interests: Hilton is best known for his discoveries in the area of cytokine signaling, particularly the isolation and cloning of an entirely novel family of negative regulators of cytokine signaling, the SOCS proteins. The Hilton lab aims to understand which of the 30,000 genes are important in the production and function of blood cells, and how this information can be used to better prevent, diagnose and treat blood cell diseases such as leukemia, arthritis and asthma.

Sandra E. Nicholson currently heads a laboratory in the Inflammation Division at the Walter & Eliza Hall Institute in Melbourne, Australia. Born in 1965, her expertise is in protein structure–function relationships and JAK/STAT signaling. Postdoctoral training: After completing a PhD at the Ludwig Institute for Tumour Biology in Melbourne (1996), Sandra Nicholson undertook postdoctoral training in the Cancer & Haematology Division at the Walter & Eliza Hall Institute (1997–2006). Academic appointments: Sandra Nicholson has been supported by an NHMRC career development award (2004–2007) and Senior Research Fellowship (2008–current), and following post-doctoral training was appointed as Laboratory Head in the Cancer & Haematology division (2006–2011). She holds an honorary appointment at the University of Melbourne. Major research interests: Sandra Nicholson is interested in understanding how SOCS box proteins negatively regulate cytokine and growth factor signaling. Her interest extends to the molecular structure of the protein complexes and how these relationships may be perturbed in inflammatory and infectious disease.

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Mini reviewSuppression of cytokine signaling: The SOCS perspective

Abstract

Section snippets

Preface

Biological role of the SOCS proteins

Biochemical mechanism of action

SOCS in disease: a case for therapeutic intervention?

Concluding remarks

Acknowledgements

Trends in Biochemical Sciences

Trends in Genetics

Biochimica et Biophysica Acta

Cell

Immunity

Cell

Immunity

Journal of Biological Chemistry

Molecular and Cellular Neurosciences

Blood

Immunity

Blood

Molecular Cell

Structure

Structure

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Biochemical and Biophysical Research Communications

Journal of Biological Chemistry

Immunity

Journal of Molecular Biology

Cellular Signalling

Immunity

Blood

Blood Reviews

Journal of Biological Chemistry

Blood

Blood

Blood

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

A family of cytokine-inducible inhibitors of signalling

Nature

A new protein containing an SH2 domain that inhibits JAK kinases

Nature

Structure and function of a new STAT-induced STAT inhibitor

Nature

A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors

EMBO Journal

Twenty proteins containing a C-terminal SOCS box form five structural classes

Proceedings of the National Academy of Sciences of the United States of America

The SOCS box-adapting proteins for ubiquitination and proteasomal degradation

IUBMB Life

The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation

Proceedings of the National Academy of Sciences of the United States of America

The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families

Genes and Development

Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1

Proceedings of the National Academy of Sciences of the United States of America

Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity

Nature Immunology

Suppressor of cytokine signaling-1 has IFN-gamma-independent actions in T cell homeostasis

Journal of Immunology

SOCS-1 regulates IL-15-driven homeostatic proliferation of antigen-naive CD8 T cells, limiting their autoimmune potential

Journal of Experimental Medicine

Gigantism in mice lacking suppressor of cytokine signalling-2

Nature

SOCS2 negatively regulates growth hormone action in vitro and in vivo

Journal of Clinical Investigation

Growth enhancement in suppressor of cytokine signaling 2 (SOCS-2)-deficient mice is dependent on signal transducer and activator of transcription 5b (STAT5b)

Molecular Endocrinology

Mini review
Suppression of cytokine signaling: The SOCS perspective