SOCS Proteins: Negative Regulators of Cytokine Signaling

  title={SOCS Proteins: Negative Regulators of Cytokine Signaling},
  author={Danielle L. Krebs and Douglas J. Hilton},
  journal={STEM CELLS},
Cytokines regulate the growth and differentiation of cells by binding to cell‐surface receptors and activating intracellular signal transduction cascades such as the JAK‐STAT pathway. Cytokine signaling is negatively regulated with respect to both magnitude and duration, and it is now clear that the suppressor of cytokine signaling (SOCS) family of proteins (SOCS1‐SOCS7 and CIS) contributes significantly to this process. Transcripts encoding CIS, SOCS1, SOCS2, and SOCS3 are upregulated in… 

The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response.

This review focuses on the suppressors of cytokine signaling (SOCS) family of cytoplasmic proteins that completes a negative feedback loop to attenuate signal transduction from cytokines that act through the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway.

The roles of SOCS3 and STAT3 in bacterial infection and inflammatory diseases

The role of SOCS3 and STAT3 expression in different cell populations in regulating the outcomes of infection and inflammatory diseases is described.

Suppressor of Cytokine Signaling 6 Associates with KIT and Regulates KIT Receptor Signaling*

The results indicate that KIT signaling is regulated by several SOCS proteins and suggest a putative function for SOCS6 as a negative regulator of receptor tyrosine kinases.

SOCS1: phosphorylation, dimerization and tumor suppression

The SOCS1-p53 tumor suppressor axis was reactivated with the SFK inhibitor dasatinib in combination with the p53 activating compound PRIMA, suggesting new avenues for cancer treatment and leaving open several new questions that deserve to be addressed.

Negative Regulator of Cytokine Signaling (SOCS) Genes in Inflammation

The results show that the proliferation and cytokine production of RA-synoviocytes in vitro is dependent on JAK/STAT3 signaling, and that these processes can be inhibited by the expression of SacS3 or dnSTAT3.

Tyrosine-phosphorylated SOCS3 Interacts with the Nck and Crk-L Adapter Proteins and Regulates Nck Activation*

It is demonstrated that SOCS3 physically interacts with the SH2/SH3-containing adapter proteins Nck and Crk-L, which are known to couple activated receptors to multiple downstream signaling pathways and the actin cytoskeleton.

Targeting Canonical and Non-Canonical STAT Signaling Pathways in Renal Diseases

Both canonical and non-canonical STAT pathways are introduced and their roles in a variety of renal diseases are introduced.

Downregulated SOCS1 expression activates the JAK1/STAT1 pathway and promotes polarization of macrophages into M1 type.

Results indicated that, when SOCS1 expression is downregulated, it will activate the JAK1/STAT1 pathway, and thereby promote the polarization of macrophages into M1 type.

Negative regulation of cytokine signaling by CIS/SOCS family proteins and their roles in inflammatory diseases.

This review focuses on the molecular mechanism of the action of CIS/SOCS family proteins and their roles in inflammatory diseases, and illustrates several approaches for treating inflammatory diseases by modulating extracellular and intracellular signaling pathways.



The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation.

It appears that the SOCS proteins may act as adaptor molecules that target activated cell signaling proteins to the protein degradation pathway, analogous to the family of F-box-containing proteins.

A family of cytokine-inducible inhibitors of signalling

Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction.

The Suppressor of Cytokine Signaling (SOCS) 1 and SOCS3 but Not SOCS2 Proteins Inhibit Interferon-mediated Antiviral and Antiproliferative Activities*

Results suggest that SOCS1 and SOCS3 but not SOCS2 are inhibitors of IFN-mediated Janus-activated kinase/signal transducers and activators of transcription (STAT) signaling pathways.

Mechanism of inhibition of growth hormone receptor signaling by suppressor of cytokine signaling proteins.

The data suggest that SOCS-1 and -3 can suppress GH-induced transcriptional activity, presumably by inhibiting the kinase activity of JAK2 either directly in the case of SOCs-1 or via binding to the tyrosine-phosphorylated GH receptor in the cases of SOCS -3.

SOCS3 Exerts Its Inhibitory Function on Interleukin-6 Signal Transduction through the SHP2 Recruitment Site of gp130*

The interplay of two inhibitors in the signal transduction pathway of interleukin-6 is analyzed and it is demonstrated that the tyrosine phosphatase SHP2 and SOCS3 do not act independently but are functionally linked.

Cutting edge: SOCS-1 is a potent inhibitor of IL-4 signal transduction.

The ability of SOCS family members to suppress IL-4 signaling is examined, and it is found that SOCS-1 potently inhibits the activation of JAK1 kinase and Stat6 in response to IL-2 and can inhibit the induction of CD23 expression byIL-4.

Suppressor of Cytokine Signaling-1 Inhibits VAV Function through Protein Degradation*

It is shown that SOCS1 has the distinct function of targeting the hematopoietic specific guanine nucleotide exchange factor, VAV, for ubiquitin-mediated protein degradation.

Cytokine-Induced Src Homology 2 Protein (Cis) Promotes T Cell Receptor–Mediated Proliferation and Prolongs Survival of Activated T Cells

The expression of CIS is selectively induced in T cells after T cell receptor (TCR) stimulation and a direct interaction of CIS and protein kinase Cθ was demonstrated, suggesting that CIS is one of the important regulators of TCR-mediated T cell activation.

Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor.

It is found that SOCS-3 interacts constitutively with IGFIR in vitro and in intact cells, and may be a direct substrate for the receptor tyrosine kinase.

Socs1 binds to multiple signalling proteins and suppresses Steel factor‐dependent proliferation

Data suggest that Socs1 is an inducible switch which modulates proliferative signals in favour of cell survival signals and functions as an adaptor protein in receptor tyrosine kinase signalling pathways.