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. 2013 Feb 27;2(1):1-29.
Print 2013.

SOCS proteins in development and disease

Monique C Trengove  1 , Alister C Ward
Affiliations

SOCS proteins in development and disease

Monique C Trengove et al. Am J Clin Exp Immunol. .

Abstract

Cytokine and growth factor signaling mediates essential roles in the differentiation, proliferation, survival and function of a number of cell lineages. This is achieved via specific receptors located on the surface of target cells, with ligand binding activating key intracellular signal transduction cascades to mediate the requisite cellular outcome. Effective resolution of receptor signaling is also essential, with excessive signaling having the potential for pathological consequences. The Suppressor of cytokine signaling (SOCS) family of proteins represent one important mechanism to extinguish cytokine and growth factor receptor signaling. There are 8 SOCS proteins in mammals; SOCS1-7 and the alternatively named Cytokine-inducible SH2-containing protein (CISH). SOCS1-3 and CISH are predominantly associated with the regulation of cytokine receptor signaling, while SOCS4-7 are more commonly involved in the control of Receptor tyrosine kinase (RTK) signaling. Individual SOCS proteins are typically induced by specific cytokines and growth factors, thereby generating a negative feedback loop. As a consequence of their regulatory properties, SOCS proteins have important functions in development and homeostasis, with increasing recognition of their role in disease, particularly their tumor suppressor and anti-inflammatory functions. This review provides a synthesis of our current understanding of the SOCS family, with an emphasis on their immune and hematopoietic roles.

Keywords: JAK-STAT; SOCS; cytokine; development; disease; growth factor; immunity; receptor tyrosine; signalling.

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Figures

Figure 1
Figure 1
Structural and functional relationships amongst SOCS proteins. SOCS proteins can be grouped into pairs with similar structure and function, and these further grouped into those mainly acting on Cytokine receptor (CytoR) signaling and those mainly acting on Receptor tyrosine kinase (RTK) signaling, reflecting evolutionary relationships. All SOCS proteins consist of three conserved domains, the N-terminal, SH2 and SOCS box domains. The N-terminal domain is the least conserved and has a variety of roles, with specific sub-domains identified in certain SOCS pairs, including the kinase inhibitory region (KIR) in SOCS1 and SOCS3 and the N-terminal conserved region (NTCR) in SOCS4 and SOCS5. The SH2 domain is lengthened by the addition of an extended SH2 sequence (ESS) and is involved in substrate binding via interaction with specific phosphotyrosine residues on the target protein. The SOCS box consists of BC box and Cul box sub-domains that recruit Elongin B and C, Cullin5, RBX1 and other E3 ligase components to mediate ubiquitination of target proteins and their subsequent proteasomal degradation.
Figure 2
Figure 2
Signaling via by cytokines and growth factors and its negative regulation by SOCS proteins. Cytokines (A) or growth factors (B) bind to their respective cell surface receptors, Cytokine receptors (CytoRs) and Receptor tyrosine kinases (RTKs), leading to receptor dimerization. For CytoRs this leads to activation of associated intracellular JAKs, which phosphorylate tyrosine residues on the receptor complex, creating docking site for STATs. These are then phosphorylated, enabling dimerization with other STATs, followed by translocation to the nucleus, where they act as transcription factors to induce expression of target genes that mediate a range of biological processes. These targets include SOCS genes capable of regulating receptor signaling, creating a negative feedback loop. RTKs possess intrinsic tyrosine kinase activity and may by-pass JAK and/or STAT activation. Individual SOCS proteins negatively regulate signaling by several mechanisms: degradation of receptors or associated proteins via the proteasomal pathway; inhibition of JAK tyrosine activity; competition for receptor phosphotyrosine residues thereby blocking other signaling molecules; prevention of nuclear translocation of key signaling molecules.
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