Role of Ubiquitylation in Controlling Suppressor of Cytokine Signalling 3 (SOCS3) Function and Expression

Abstract

The realisation that unregulated activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is a key driver of a wide range of diseases has identified its components as targets for therapeutic intervention by small molecule inhibitors and biologicals. In this review, we discuss JAK-STAT signalling pathway inhibition by the inducible inhibitor "suppressor of cytokine signaling 3 (SOCS3), its role in diseases such as myeloproliferative disorders, and its function as part of a multi-subunit E3 ubiquitin ligase complex. In addition, we highlight potential applications of these insights into SOCS3-based therapeutic strategies for management of conditions such as vascular re-stenosis associated with acute vascular injury, where there is strong evidence that multiple processes involved in disease progression could be attenuated by localized potentiation of SOCS3 expression levels.

Figure 1

SOCS3-mediated inhibition of IL-6 signalling interaction of IL-6 with a membrane-bound IL-6 receptor (IL-6Rα) and gp130 dimers triggers activation of gp130-bound JAKs, which then phosphorylate gp130 on key cytoplasmic Tyr residues that act as docking sites for SH2 domain-mediated interaction with target proteins. These include four pYXXQ motifs that recruit STAT proteins (predominantly STAT3) and a pY⁷⁵⁹STV (human sequence) motif responsible for binding protein Tyr phosphatase SHP2. Recruited SHP2 and STATs are then phosphorylated by activated JAKs (e.g., STAT3 is phosphorylated on Tyr705). JAK-phosphorylated STATs then dimerise and translocate to the nucleus to initiate transcription of target genes. One of the induced genes encodes SOCS3, which can then interact with Tyr759-phosphorylated gp130 to terminate IL-6 signalling predominantly via two mechanisms; KIR (kinase inhibitory region)-mediated inhibition of receptor-bound JAKs (1), and formation of an E3 ubiquitin ligase complex that ubiquitylates target proteins for subsequent degradation by the proteasome (2).

Figure 2

Structural organisation and homology modelling of an ECS^SOCS3 complex A. Organisation of domains within SOCS3: the numbering is for human SOCS3. Domains include an extended N-terminal region, the kinase inhibitory region (KIR), an extended SH2 sub-domain (ESS) which precedes the central SH2 domain, and the SOCS box, which includes BC box and Cul box sub-domains important for binding the elongins and cullin proteins and forming the E3 ubiquitin ligase complex. Also labelled is a PEST sequence within the C-terminal region of the SH2 domain. B. Structural homology model of the ECS^SOCS3 E3 ubiquitin ligase complex. The central cullin 5 scaffold protein positions the E2 conjugating enzyme in close proximity to SOCS3, which binds a target substrate (not shown) via its SH2 domain. SOCS3 is attached to cullin 5 both directly (via the Cul box) and indirectly through the elongin B/elongin C heterodimer. The triple α-helical structure of the C-terminal domain SOCS box forms a four-helix bundle with α-helix 4 of elongin C. Reproduced from [28]. You jumped the numbers in between.with permission.