SOCS2 Can Enhance Interleukin-2 (IL-2) and IL-3 Signaling by Accelerating SOCS3 Degradation

Abstract

Cytokine responses can be regulated by a family of proteins termed suppressors of cytokine signaling (SOCS) which can inhibit the JAK/STAT pathway in a classical negative-feedback manner. While the SOCS are thought to target signaling intermediates for degradation, relatively little is known about how their turnover is regulated. Unlike other SOCS family members, we find that SOCS2 can enhance interleukin-2 (IL-2)-and IL-3-induced STAT phosphorylation following and potentiate proliferation in response to cytokine stimulation. As a clear mechanism for these effects, we demonstrate that expression of SOCS2 results in marked proteasome-dependent reduction of SOCS3 and SOCS1 protein expression. Furthermore, we provide evidence that this degradation is dependent on the presence of an intact SOCS box and that the loss of SOCS3 is enhanced by coexpression of elongin B/C. This suggests that SOCS2 can bind to SOCS3 and elongin B/C to form an E3 ligase complex resulting in the degradation of SOCS3. Therefore, SOCS2 can enhance cytokine responses by accelerating proteasome-dependent turnover of SOCS3, suggesting a mechanism for the gigantism observed in SOCS2 transgenic mice.Cytokines such as interleukin-2 (IL-2) regulate the immune response via interaction with cell surface receptors on target cells. These receptors interact with cytoplasmic tyrosine kinases, specifically, members of the Janus kinase (JAK) family, which subsequently phosphorylate signal transducer and activator of transcription (STAT) proteins. Phosphorylation of STATs results in their dimerization and translocation to the nucleus and subsequent transcriptional activation of genes important for proliferation and differentiation (11). Inhibition of these signaling pathways is crucial for the control of the inflammatory response (16). The suppressors of cytokine signaling (SOCS/SSI/CIS) are thought to play a key role in this process and are upregulated by and inhibit the JAK/STAT pathway in a classic negative-feedback manner (7,32,39). Eight SOCS family proteins have been described, CIS (cytokine-inducible SH2 domain-containing protein) and SOCS1 to SOCS7 (10,22,29). These proteins are characterized by two common structural motifs, an SH2 domain and a C-terminal SOCS box. The SOCS box is thought to interact with elongin B/C, part of an E3 ubiquitin ligase complex that targets associated proteins for degradation through the ubiquitin pathway (27). As well as SOCS, a number of other protein subfamilies including the von Hippel-Lindau (VHL) tumor suppressor protein contain this SOCS box motif, indicating that it may have an important and conserved role (17). The SOCS box of VHL associates with an E3 ligase complex and induces the proteasomal degradation of hypoxia-inducible factor 1␣ (40).More recently, Asb, an adipocyte-specific ankyrin and SOCS box-containing protein, has been shown to interact with the adaptor protein APS (adapter protein with PH and SH2 domain) to enable recruitment of elongin B/C to the insulin receptor (43).SOCS1 and SOCS3 are induced ra...

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

“…In addition, recent studies demonstrated regulatory cross-talk between SOCS family members. For example, Tannahill et al (67) found that SOCS2 can accelerate SOCS3 proteasomal degradation in Ba/F3 cells by binding with both Elongin C and SOCS3. Our data are consistent with a similar role for SOCS2 in RCC in this study.…”

“…Finally, SOCS proteins bind the Elongin C component of the ubiquitin ligase complex, which stabilizes SOCS, and leads to proteasomal degradation of SOCS-bound proteins, including JAKs. A recent report from Tannahill et al (67) demonstrates that SOCS3 and SOCS2 heterodimerize, and binding of the complex to Elongin C led to SOCS2 stabilization and SOCS3 degradation.…”

SOCS2: inhibitor of JAK2V617F-mediated signal transduction

“…SOCS2 is not only reported to inhibit contact between class I cytokine receptors and JAK2, 25 but is also reported to accelerate proteasome-dependent turnover of SOCS3. 27 In the latter scenario, expression of SOCS2 would lead to silencing of JAK2V617F through its SOCS3-degrading effect. SOCS3, a well-known inhibitor of wild-type JAK2, potentiates the activity of JAK2V617F.…”

SOCS2 (suppressor of cytokine signaling 2)

“…Being an E3 ligase, SOCS2 regulates a number of proteins highly implicated in regulation of immune responses such as FoxP3 (Knosp et al, 2013) and TRAF6 (McBerry et al, 2012). SOCS2 also accelerates degradation of other members of the SOCS family such as SOCS1 and SOCS3 thus further impinging on downstream STAT signaling (Piessevaux et al, 2006;Tannahill et al, 2005). In turn, SOCS2 gene itself is under regulation of various inflammatory signals (e.g., LPS, dioxins, LipoxinA4) (Machado et al, 2006;Hu et al, 2009bHu et al, , 2012 and cytokines (e.g.,IL-4, IL-10, IFNβ, IFNγ) (Knosp et al, 2011;Posselt et al, 2011).…”