Suppression of cytokine signaling: the SOCS perspective

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.

Keywords: Cytokine; JAK; Receptor; SOCS; SOCS box.

Fig. 1. Domain architecture of the SOCS family of proteins

The SOCS proteins contain a C-terminal SOCS box motif, a central SH2-domain and an N-terminal region of varied length and amino acid composition. The SOCS are shown in pairs based on the amino acid sequence homology between their SH2 domains. Key features are distinguished by color and are enumerated in the legend, including a recently identified conserved region in the N-termini of SOCS4 and SOCS5 [86]. Abbreviations: kinase inhibitory region (KIR), extended SH2 domain (ESS), proline, glutamic acid, serine and threonine (PEST) rich region.

Fig. 2. Structural analysis of the SOCS3/JAK2/gp130 complex

A) Schematic representation of the JAK/gp130/SOCS3 tripartite complex. JAK2 and SOCS3 can bind independently to the gp130 receptor subunit via their FERM and SH2 domains, respectively. A second interaction interface between SOCS3 (KIR-ESS-SH2) and JAK2 (JH1) completes the high-affinity ternary complex and facilitates the inhibition of JAK. B) The JAK2/SOCS3 interaction. The JAK2 binding epitope, centered on the GQM motif, is shown as an electrostatic surface, with SOCS3 shown as a ribbon diagram (green). Residues from the SOCS3-SH2 domain (BC loop), ESS and KIR all contribute to the binding interface. The critical phenylalanine (Phe25) of the SOCS3 KIR sits in a hydrophobic pocket between the JAK2 activation loop and the GQM motif. C) Ribbon diagram of the SOCS3-SH2 domain (green) bound simultaneously to gp130Tyr757 (black) and the JH1 domain of JAK2 (beige). The SOCS3/JAK interaction occurs on the opposite face to the SOCS3 /gp130pY757 tyrosine. (B) & (C) are reproduced with permission from Kershaw et al., [63].