Functional Cross-modulation between SOCS Proteins Can Stimulate Cytokine Signaling
Journal of Biological Chemistry
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
... 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. http://www.jbc.org/ Downloaded from FIGURE 8. SOCS2, SOCS6, and SOCS7 interact with the SOCS boxes of all SOCS family members. HEK293-T cells were transiently cotransfected with plasmids encoding bait variants of the SOCS boxes of all SOCS proteins or the chimeric EpoR-LR-F3 construct as a negative control; the pMG2-SOCS2, pMG2-SOCS6, pMG2-SOCS7, or pMG2-CIS prey; and the pXP2d2-rPAP1-luciferase reporter. After transfection, cells were either left untreated or were stimulated with erythropoietin (Epo) for 24 h. Luciferase activities were measured in triplicate. Data are expressed as -fold induction (stimulated/non-stimulated). Downloaded from FIGURE 10. SOCS6, but not SOCS6(LC-QQ), promotes degradation of SOCS1. Increasing concentrations of FLAG-tagged SOCS6 or SOCS6(LC-QQ) were coexpressed transiently in HEK293-T cells with FLAG-tagged SOCS1. Cells were treated with cycloheximide (20 M) for up to 6 h. The lysates were blotted for SOCS1 and SOCS6 expression with anti-FLAG antibody.