TY - JOUR
T1 - Identification of critical residues required for suppressor of cytokine signaling-specific regulation of interleukin-4 signaling
AU - Haque, S. Jaharul
AU - Harbor, Phyllis C.
AU - Williams, Bryan R.G.
PY - 2000/8/25
Y1 - 2000/8/25
N2 - Suppressor of cytokine signaling (SOCS) family proreins were originally identified as cytokine-induced negative regulators of cytokine signaling. We show that SOCS-1 and SOCS-3 inhibit interleukin (IL)-4-dependent signal transducer and activator of transcription 6 (Stat6) activation of and subsequent gene induction. By contrast, SOCS-2 and cytokine-inducible Src homology domain 2 (SH2)-containing protein up-regulate these processes. IL-4 initiates transmembrane signaling through two types of receptor complexes comprising the IL-4Rα subunit and the associated Janus kinase 1 (Jak1) as common essential components. We demonstrate that both SOCS-1- and SOCS-3-mediated down-regulation of IL-4 signaling is due to an inhibition of the receptor associated Jak1 activity. The SOCS proteins contain an amino-terminal region of variable length and primary structure, a central SH2 domain, and a carboxyl-terminal conserved motif termed SOCS-box. We show that the SH2 domains of SOCS-2, SOCS-3, and cytokine-inducible SH2-containing protein are functionally redundant in regulating the IL-4-dependent Jak-Stat signaling. The Pre-SH2 domains of SOCS-2 and SOCS-3 confer the specificity of their regulatory function. Importantly, the Pre-SH2 domain of SOCS-3 alone can inhibit IL-4 signaling. The SH2-proximal 25 amino acids of SOCS-3 are sufficient for this inhibition, and the Thr residue at position 24 and the Phe residue at position 25 are individually indispensable for its inhibitory function. Thus, the Thr-Phe motif in the Pre-SH2 domain plays a critical role in SOCS-3-mediated inhibition of the IL-4-dependent Jak-Star signaling, likely by regulating the mode of SOCS-Jak interaction.
AB - Suppressor of cytokine signaling (SOCS) family proreins were originally identified as cytokine-induced negative regulators of cytokine signaling. We show that SOCS-1 and SOCS-3 inhibit interleukin (IL)-4-dependent signal transducer and activator of transcription 6 (Stat6) activation of and subsequent gene induction. By contrast, SOCS-2 and cytokine-inducible Src homology domain 2 (SH2)-containing protein up-regulate these processes. IL-4 initiates transmembrane signaling through two types of receptor complexes comprising the IL-4Rα subunit and the associated Janus kinase 1 (Jak1) as common essential components. We demonstrate that both SOCS-1- and SOCS-3-mediated down-regulation of IL-4 signaling is due to an inhibition of the receptor associated Jak1 activity. The SOCS proteins contain an amino-terminal region of variable length and primary structure, a central SH2 domain, and a carboxyl-terminal conserved motif termed SOCS-box. We show that the SH2 domains of SOCS-2, SOCS-3, and cytokine-inducible SH2-containing protein are functionally redundant in regulating the IL-4-dependent Jak-Stat signaling. The Pre-SH2 domains of SOCS-2 and SOCS-3 confer the specificity of their regulatory function. Importantly, the Pre-SH2 domain of SOCS-3 alone can inhibit IL-4 signaling. The SH2-proximal 25 amino acids of SOCS-3 are sufficient for this inhibition, and the Thr residue at position 24 and the Phe residue at position 25 are individually indispensable for its inhibitory function. Thus, the Thr-Phe motif in the Pre-SH2 domain plays a critical role in SOCS-3-mediated inhibition of the IL-4-dependent Jak-Star signaling, likely by regulating the mode of SOCS-Jak interaction.
UR - http://www.scopus.com/inward/record.url?scp=0034714399&partnerID=8YFLogxK
U2 - 10.1074/jbc.275.34.26500
DO - 10.1074/jbc.275.34.26500
M3 - Article
C2 - 10950967
AN - SCOPUS:0034714399
SN - 0021-9258
VL - 275
SP - 26500
EP - 26506
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 34
ER -