Functional Cross-modulation between SOCS Proteins Can Stimulate Cytokine Signaling

Abstract

SOCS (suppressors of cytokine signaling) proteins are negative regulators of cytokine signaling that function primarily at the receptor level. Remarkably, in vitro and in vivo observations revealed both inhibitory and stimulatory effects of SOCS2 on growth hormone signaling, suggesting an additional regulatory level. In this study, we examined the possibility of direct crossmodulation between SOCS proteins and found that SOCS2 could interfere with the inhibitory actions of other SOCS proteins in growth hormone, interferon, and leptin signaling. This SOCS2 effect was SOCS box-dependent, required recruitment of the elongin BC complex, and coincided with degradation of target SOCS proteins. Detailed mammalian protein-protein interaction trap (MAPPIT) analysis indicated that SOCS2 can interact with all members of the SOCS family. SOCS2 may thus function as a molecular bridge between a ubiquitin-protein isopeptide ligase complex and SOCS proteins, targeting them for proteasomal turnover. We furthermore extended these observations to SOCS6 and SOCS7. Our findings point to a unique regulatory role for SOCS2, SOCS6, and SOCS7 within the SOCS family and provide an explanation for the unexpected phenotypes observed in SOCS2 and SOCS6 transgenic mice.Cytokine signaling is typically a transient event, implying rapid and finely tuned attenuation. Receptor binding leads to rapid activation of receptor-associated members of the JAK 3 family. Subsequent phosphorylation of tyrosine residues in the receptor tails enables recruitment of downstream signaling molecules whereby STATs play a prominent role. Activated STATs translocate to the nucleus, where they control cytokineregulated gene transcription. Negative control occurs at many levels and involves receptor down-regulation, protein-tyrosine phosphatases, protein inhibitors of activated STATs, and members of the SOCS (suppressors of cytokine signaling) protein family.The SOCS family consists of eight different members (SOCS1-7 and CIS (cytokine-inducible SH2 domain-containing protein)) characterized by conserved structural features. All SOCS proteins consist of a central SH2 domain flanked by a variable N-terminal region and a conserved C-terminal SOCS box (1, 2). The SH2 domain can inhibit STAT activation by direct competition for the phosphorylated receptor recruitment sites (3-8). SOCS1 and SOCS3 carry an additional kinase inhibitory region (KIR) in their N-terminal domains that acts as a pseudosubstrate for the JAK kinase, thereby blocking signaling (5). The SOCS box was shown to act as an interaction domain for the elongin BC complex (9, 10), which, in turn, is a component of an ubiquitin-protein isopeptide ligase (E3) complex (11). This way, the SOCS box can control protein turnover by marking target proteins for proteasomal degradation (12). However, the significance of the interaction between SOCS proteins and the elongin BC complex is not totally clarified, as some reports propose that elongin association targets SOCS molecules for proteasomal degradation (10,(12)(13)...

Neuroendocrine hormones such as growth hormone and prolactin are integral members of the immunological cytokine network

“…For example, it is clear that SOCS2 is a key player in normal GH feedback inhibition since Socs2 −/− mice exhibit gigantism and are 30-40% larger than normal littermates [44] [45]. However, there are other layers of complexity since SOCS proteins can also target SOCS proteins for degradation [46]. Thus, Socs2Tg mice that over express SOCS2 are not dwarf mice but instead are also larger than normal littermates [47] [48].…”

Constitutive expression of suppressor of cytokine signalling-3 in skeletal muscle leads to reduced mobility and overweight in mice

“…Indeed, it has been shown that chemokine CXC ligand-5 induces insulin resistance mainly by inhibiting insulin signalling in muscle, which may be driven by SOCS-2 production [36]. Moreover, a given SOCS protein appears to promote the proteasomal degradation of other SOCS proteins [37]. This suggests that SOCS proteins are able to transregulate the expression of other members of the family, leading to auto-regulatory compensatory mechanisms.…”

Cross-Regulation of JAK-STAT Signaling: Implications for Approaches to Combat Chronic Inflammatory Diseases and Cancers

“…An additional level of complexity demonstrated by SOCS proteins is their ability to interact with other SOCS family members (Piessevaux et al, 2006;Tannahill et al, 2005). For example, although SOCS2 plays a major role in the negative regulation of GH signaling (Greenhalgh et al, 2002), it has also been shown to enhance GH signaling.…”