The biology and mechanism of action of suppressor of cytokine signaling 3

Abstract

Suppressors of cytokine signaling 3 (SOCS3) has been shown to be an important and non-redundant feedback inhibitor of several cytokines including leukemia inhibitory factor, IL-6, IL-11, Ciliary neurotrophic factor (CNTF), leptin, and granulocyte colony-stimulating factor (G-CSF). Loss of SOCS3 in vivo has profound effects on placental development, inflammation, fat-induced weight gain, and insulin sensitivity. SOCS3 expression is induced by Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling and it then binds to specific cytokine receptors (including gp130, G-CSF, and leptin receptors). SOCS3 then inhibits JAK/STAT signaling in two distinct ways. First, SOCS3 is able to directly inhibit the catalytic activity of JAK1, JAK2, or TYK2 while remaining bound to the cytokine receptor. Second, SOCS3 recruits elongins B/C and Cullin5 to generate an E3 ligase that ubiquitinates both JAK and cytokine receptor targeting them for proteasomal degradation. Detailed in vivo studies have revealed that SOCS3 action not only limits the duration of cytokine signaling to prevent overactivity but it is also important in maintaining the specificity of cytokine signaling.

Figure 1

Negative feedback regulation of JAK/STAT signaling. Cytokine binding to specific receptors activates associated Janus Kinases (JAKs) which then tyrosine phosphorylate the intracellular domain of the receptor. These newly phosphorylated tyrosine residues on the receptor recruit the STAT family of transcription factors. STATs normally reside in the cytoplasm in an inactive state however, once bound to the receptor, they are activated by JAK and then dimerise and translocate into the nucleus where they initiate transcription of cytokine-responsive genes. SOCS3 is one of the proteins whose expression is upregulated by STAT and it then feeds back into the signaling cascade thereby inhibiting signaling and allowing the cell to return to its basal state.

Figure 2. The structure of SOCS3

SOCS3 can be divided into three overall domains: The N-terminal domain (Residues 1-29, including the KIR-residues 22-29), the extended SH2 domain (Residues 30-185) and the SOCS box (Residues 186-225). An atomic resolution structure exists of the extended SH2 domain (which includes the SH2 domain, blue and the ESS helix, white) of SOCS3 bound to a phospho-peptide from the gp130 receptor (red) (PDB ID: 2HMH) (8). The phosphotyrosine of gp130 is indicated (pTyr), as are three important valines: V−2, V+3 and V+4 (numbers indicate position relative to pTyr). The SOCS box of SOCS3 can be modeled on that of SOCS2 (PDB ID: 2C9W) (14) and is shown above in green. Important residues are labeled. Note that the kinase inhibitory region is unstructured and is shown as a dotted line that joins the ESS helix. The PEST motif is also unstructured.

Figure 3

The JAK insertion loop and the GQM motif that encodes specificity for SOCS3 is not present in JAK3.

Figure 4. A model for SOCS3 inhibition of JAK/STAT signalling

For clarity, the IL-6 receptor alpha chains are omitted and only the JAK binding (gp130) chains are shown.