SOCS-3 inhibits IL-12-induced STAT4 activation by binding through its SH2 domain to the STAT4 docking site in the IL-12 receptor beta2 subunit.
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.
Yamamoto
Koh
K
Department of Hematology and Oncology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Yamaguchi
Mitsuko
M
Miyasaka
Nobuyuki
N
Miura
Osamu
O
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000502:physiology*; D018123:Receptors, Interleukin / Q000737:chemistry / Q000378:metabolism*; D053707:Receptors, Interleukin-12; D012097:Repressor Proteins; D050797:STAT4 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D017931:DNA Primers; D004268:DNA-Binding Proteins; C508439:IL12RB2 protein, human; D011506:Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D018664:Interleukin-12; D014443:Tyrosine