SOCS-3 inhibits IL-12-induced STAT4 activation by binding through its SH2 domain to the STAT4 docking site in the IL-12 receptor β2 subunit

• DOI: 10.1016/j.bbrc.2003.09.140
• Publication Date: 2003-10-15T13:17:29Z
• Authors: Koh Yamamoto; Mitsuko Yamaguchi; Nobuyuki Miyasaka; Osamu Miura
• Keywords: Binding Sites; Base Sequence; Receptors, Interleukin-12; Proteins; Suppressor of Cytokine Signaling Proteins; Receptors, Interleukin; STAT4 Transcription Factor; Interleukin-12; Cell Line; DNA-Binding Proteins; Repressor Proteins; 03 medical and health sciences; 0302 clinical medicine; Suppressor of Cytokine Signaling 3 Protein; Trans-Activators; Animals; Humans; Tyrosine; Phosphorylation; DNA Primers; Protein Binding; Transcription Factors

IL-12 promotes the proliferation of T cells as well as NK cells and plays a critical role in induction of the Th1 differentiation. IL-12 mediates its biological activities through activation of the receptor-associated JAK family kinases and STAT4, which is recruited to phosphorylated Tyr-800 in the human IL-12 receptor beta2 subunit (IL-12Rbeta2). Here we demonstrate that suppressor of cytokine signaling-3 (SOCS-3) is also recruited to IL-12Rbeta2 by the interaction involving the SOCS-3 SH2 domain and phosphorylated Tyr-800 in IL-12Rbeta2. Furthermore, SOCS-3, but not its SH2 domain-defective mutant, inhibited the IL-12-induced activation of DNA-binding and transcriptional activities of STAT4. These results suggest that SOCS-3, expressed at high levels in Th2 cells, plays an inhibitory role in STAT4-mediated IL-12 signaling by binding to the STAT4 docking site in IL-12Rbeta2, thus raising a possibility that SOCS-3 may play a role in regulation of Th differentiation.