SOCS2 can enhance interleukin-2 (IL-2) and IL-3 signaling by accelerating SOCS3 degradation

Infection and Immunity Group, Centre for Cancer Research and Cell Biology, Queens University, Belfast, UK.
Molecular and Cellular Biology (Impact Factor: 4.78). 11/2005; 25(20):9115-26. DOI: 10.1128/MCB.25.20.9115-9126.2005
Source: PubMed


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.

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    • "SOCS2, SOCS6, and SOCS7 appear to form a subgroup of the SOCS family that have been shown to interact with the SOCS box of all members of the SOCS family and may be required to regulate the stability of other SOCS proteins (Piessevaux et al., 2006). This cross regulation might enable late-induction SOCS proteins (such as SOCS2) to down regulate early-induction SOCS proteins (such as CIS, SOCS1, and SOCS3) so the cell can restore sensitivity to future cytokine stimulation (Tannahill et al., 2005; Piessevaux et al., 2006). "
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    ABSTRACT: The classic neurotrophins Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF) and Neurotrophins NT-3 and NT-4 are well known to regulate various aspects of neuronal differentiation, survival and growth. They do this by binding to their cognate receptors, members of the Tropomyosin-related kinase (Trk) receptor tyrosine kinase family, namely TrkA, TrkB, and TrkC. These receptors are then internalized and localized to different cellular compartments, where signal transduction occurs. Conversely, members of the suppressor of cytokine signaling (SOCS) family are best known as negative regulators of signaling via the JAK/STAT pathway. Some members of the family, and in particular SOCS2, have roles in the nervous system that at least partially overlap with that of neurotrophins, namely neuronal differentiation and neurite outgrowth. Recent evidence suggests that SOCS2 is a novel regulator of NGF signaling, altering TrkA cellular localization and downstream signaling to affect neurite growth but not neuronal survival. This review first discusses regulation of Trk receptor signaling, followed by the role of SOCS2 in the nervous system and finishes with a discussion of possible mechanisms by which SOCS2 may regulate TrkA function.
    Frontiers in Molecular Neuroscience 05/2014; 7:39. DOI:10.3389/fnmol.2014.00039 · 4.08 Impact Factor
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    • "SOCS2 and SOCS3 may act antagonistically: SOCS2 controls T-cell polarization, repressing Th2, but supporting Th17 differentiation, while SOCS3 plays opposing roles [42]. It has been shown that SOCS2 increases and prolongs STAT5 phosphorylation induced by IL-2/3 [41]–[43] which, in turn, increases proliferation, while SOCS3 reduces pSTAT5 levels, JAK2 mutant cases excepted [44]. "
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    ABSTRACT: Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they reportedly promote JAK2-oligomerization and autonomous signalling, Affected entities are promising candidates for therapy with JAK2 signalling inhibitors. While JAK2-translocations occur in myeloid, B-cell and T-cell lymphoid neoplasms, our findings suggest their incidence among the last group is low. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in a trio of cell lines established at indolent (MAC-1) and aggressive (MAC-2A/2B) phases of a cutaneous T-cell lymphoma (CTCL). To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 top upregulated genes in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2, highlighting its role as a central signalling target of JAK2 translocation neoplasia. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive lymphoma cells, was partially restored by PCM1-JAK2 knockdown. Treatment with a selective JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive confirmed knockdown results and highlighted JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5, supporting a general paradigm of STAT5 activation by JAK2 alterations in lymphoid malignancies. MAC-1/2A/2B - the first JAK2-translocation leukemia/lymphoma cell lines described - display conspicuous JAK/STAT signalling accompanied by T-cell developmental and autoimmune disease gene expression signatures, confirming their fitness as CTCL disease models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements.
    PLoS ONE 01/2013; 8(1):e53767. DOI:10.1371/journal.pone.0053767 · 3.23 Impact Factor
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    • "The interaction between SOCS1 and Elongin B/C complex presumably contributed to the degradation of SOCS1 [38]–[40]. Recent studies demonstrated that SOCS2 bound to the SOCS box of all SOCS family, which accelerated the turnover of SOCS proteins [41]. The levels of SOCS1, as a potent signaling inhibitor, must be tightly regulated. "
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    ABSTRACT: Interferon (IFN)-induced Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway is important in controlling immune responses and is negatively response-regulated by the suppressor of cytokine signaling (SOCS) proteins. However, several viruses have developed various strategies to inhibit this pathway to circumvent the anti-viral immunity of the host. The infectious spleen and kidney necrosis virus (ISKNV) is the type species of the genus Megalocytivirus in the family Iridoviridae and a causative agent of epizootics in fish. ISKNV ORF103R encodes a predicted viral SOCS (vSOCS) with high homology to the vertebrate SOCS1, but lacks a SOCS-box domain. Interestingly, vSOCS only exists in the genus Megalocytivirus. ISKNV-vSOCS can block the IFN-α-induced Jak/Stat pathway in HepG2 cells. Over-expression of ISKNV-vSOCS inhibited the activities of IFN-stimulated response element (ISRE) promoter; however, the inhibitions by ISKNV-vSOCS were dose-dependent. ISKNV-vSOCS interacted with Jak1 protein and inhibited its tyrosine kinase activity in vitro. ISKNV-vSOCS also impaired the phosphorylation of Stat1 and Stat3 proteins and suppressed their activations. The point mutations (F18D, S66A, S85A, and R64K) of ISKNV-vSOCS significantly impaired the inhibition of IFN-α-induced ISRE-promoter activation. In conclusion, vSOCS inhibits IFN-α-induced Stat1/Stat3 signaling, suggesting that Megalocytivirus has developed a novel strategy to evade IFN anti-viral immunity via vSOCS protein.
    PLoS ONE 07/2012; 7(7):e41092. DOI:10.1371/journal.pone.0041092 · 3.23 Impact Factor
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