SOCS regulation of the JAK/STAT signalling pathway

Abstract

The suppressor of cytokine signalling (SOCS) proteins were, as their name suggests, first described as inhibitors of cytokine signalling. While their actions clearly now extend to other intracellular pathways, they remain key negative regulators of cytokine and growth factor signalling. In this review we focus on the mechanics of SOCS action and the complexities of the mouse models that have underpinned our current understanding of SOCS biology.

Figure 1. Mechanism of SOCS action

In general, cytokine binding to a cognate receptor results in activation of the JAK/STAT pathway and induction of Socs gene transcription in a STAT-dependent manner. The SOCS proteins then inhibit signalling either by direct inhibition of JAK kinase activity (SOCS1: S1), SH2-recruitment to the receptor cytoplasmic domain, followed by inhibition of JAK activity (SOCS3: S3), or by competition with STAT-SH2 domains for specific receptor phosphotyrosine residues (CIS, SOCS2). An additional level of regulation is provided by an E3 ubiquitin-ligase complex bound to the SOCS box motif, which ubiquitinates the associated proteins targeting them for proteasomal degradation (inset).

Figure 2. A unique SH2 domain

Top panel: Ribbon diagram of the SOCS3 SH2-domain showing interaction of the ESS (grey) with the phosphotyrosine binding loop (reproduced with permission from Elsevier Press) [44]. Bottom panel: Amino acid alignment encompassing KIR, ESS and N-SH2 domain boundaries and highlighting residues critical for SOCS1 and SOCS3 function (*), residues conserved between SOCS1, 3, 4, 5 and Tkip (blue background), conserved between CIS, SOCS1-7 (green background), or conserved between SOCS5 and Tkip (purple font).