Regulation of multiple cytokine signalling pathways by SOCS3 is independent of SOCS2

Abstract

Suppressor of cytokine signalling (SOCS) 3 is an essential regulator of cytokine signalling, and in turn its expression is tightly regulated. Data from overexpression studies in cell lines suggest that SOCS2 regulates SOCS3 protein degradation, by forming a molecular bridge to an E3 ubiquitinligase complex. Whether this regulation is relevant in primary cells is unknown. In this study, we utilized Socs2 −/− mice to examine the role of SOCS2 in modulating SOCS3 expression and degradation, and its impact on IL-2 and IL-6 signalling in primary haemopoietic cells. Both biochemical and biological analyses demonstrated unperturbed SOCS3 expression and cytokine signalling in the absence of SOCS2. Our results suggest that SOCS2 is not a physiological regulator of SOCS3 expression and action in primary haemopoietic cells.

Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function

“…Interestingly, SOCS2 expression in lymphocytes appears much later than some other SOCS family members [44], perhaps indicating a delayed counter-regulatory role for SOCS2 [18,43]. However the absence of SOCS2 in primary hematopoetic cells did not appear to affect the levels of SOCS3 [49], indicating that the role of SOCS2 in T cell biology, if any, is unclear.…”

“…The ectopic expression of SOCS2 appears to not only degrade SOCS3, but also enhance IL-2, IL-3, and growth hormone (GH) signaling [44,45]. However, the physiological role of SOCS2 remains unclear as both its deletion and overexpression appear to enhance GH signaling, resulting in gigantism [46-48] and furthermore the absence of SOCS2 does not appear to impact SOCS3 levels in hematopoetic cells [49]. These findings indicate that SOCS2, SOCS6 and SOCS7 might counter-regulate other SOCS family members, although the role of this counter-regulation has not been fully elucidated.…”

Erythropoietin receptor response circuits

“…In particular, SOCS-3 and and/or CIS may inhibit JAK2 [113–115], and SOCS-3 and -2 further have been proposed to cross-regulate [116]. In ES cells, however, SOCS-3’s actions recently have been shown to be sustained in the absence of SOCS-2 [117]. This is of potential clinical significance in that dysregulation via SOCS-3 hyper-phosphorylation may result from JAK2-V617F mutation, and this may limit SOCS-3’s suppressing activity [112].…”