Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction

Abstract

SOCS-1 was originally identified as an inhibitor of interleukin-6 signal transduction and is a member of a family of proteins (SOCS-1 to SOCS-7 and CIS) that contain an SH2 domain and a conserved carboxyl-terminal SOCS box motif. Mutation studies have established that critical contributions from both the amino-terminal and SH2 domains are essential for SOCS-1 and SOCS-3 to inhibit cytokine signaling. Inhibition of cytokinedependent activation of STAT3 occurred in cells expressing either SOCS-1 or SOCS-3, but unlike SOCS-1, SOCS-3 did not directly interact with or inhibit the activity of JAK kinases. Although the conserved SOCS box motif appeared to be dispensable for SOCS-1 and SOCS-3 action when overexpressed, this domain interacts with elongin proteins and may be important in regulating protein turnover. In gene knockout studies, SOCS-1 -/-mice were born but failed to thrive and died within 3 weeks of age with fatty degeneration of the liver and hemopoietic infiltration of several organs. The thymus in SOCS-1 -/-mice was small, the animals were lymphopenic, and deficiencies in B lymphocytes were evident within hemopoietic organs. We propose that the absence of SOCS-1 in these mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects. J. Leukoc. Biol. 66: 588-592; 1999.

In vivo actin cross-linking induced by Vibrio cholerae type VI secretion system is associated with intestinal inflammation

“…Cell adhesion molecule gene Icam1 was more highly expressed in ATM-1-infected mice, and this receptor is associated with leukocyte migration. ATM-1 induced higher expression of genes that regulate inflammation, including Nfkbia, Atf3, Socs3, and zinc finger proteins tristertrapolin (Zfp36) and Zc3h12a, which destabilize mRNA transcripts of proinflammatory cytokines (30)(31)(32)(33). This is consistent, because during activation of inflammation there is also concomitant negative regulation that dampens the immune response and aids in resolution of inflammation.…”

Immunohistochemical detection of tyrosine phosphatase SHP‐1 predicts outcome after radical prostatectomy for localized prostate cancer

“…54 The suppressors of cytokine signaling-1 (SOCS-1) and SOCS-3 are regulatory proteins involved in terminating IL-6 signaling by inhibiting the JAK/STAT pathway. 55 SOCS-1 expression is increased by IL-6 in prostate cancer cell lines, and it has been shown that SOCS-1 has a growth-inhibitory effect in these cells. SOCS-1 down-regulation did not, however, prevent IL-6 induced growth inhibition of LNCaP cells.…”

SOCS-6 Negatively Regulates T Cell Activation through Targeting p56 to Proteasomal Degradation

“…EF/BOS plasmids expressing SOCS-1, SOCS-2, SOCS-3, and CIS were obtained from Dr. Tracy A. Willson (35). As baits for the yeast two-hybrid assay, corresponding DNA fragments were amplified by PCR with Pyrobest enzyme (Takara) using primers with EcoRI (5Ј-primer) or BamHI (3Ј-primer) site extension.…”

“…SOCS-6 and deletion mutants were synthesized in the presence of [ 35 S]methionine using TNT T7-quick coupled transcription/translation kit (Promega). 35 SLabeled proteins were mixed with immobilized GST or GST fusion protein in 1 ml of binding buffer (phosphate-buffered saline containing 0.25% Nonidet P-40) and incubated at 4°C for 1 h. After five washes with 1 ml binding buffer, bound proteins were eluted with SDS sample buffer, separated on 4 -20% SDS-PAGE, and analyzed by autoradiography.…”