In general, cytokine binding to a cognate receptor results in activation of the JAK/STAT pathway and induction of Socs gene transcription in a STAT-dependent manner. The SOCS proteins then inhibit signalling either by direct inhibition of JAK kinase activity (SOCS1: S1), SH2-recruitment to the receptor cytoplasmic domain, followed by inhibition of JAK activity (SOCS3: S3), or by competition with STAT-SH2 domains for specific receptor phosphotyrosine residues (CIS, SOCS2). An additional level of regulation is provided by an E3 ubiquitin-ligase complex bound to the SOCS box motif, which ubiquitinates the associated proteins targeting them for proteasomal degradation (inset).

Top panel: Ribbon diagram of the SOCS3 SH2-domain showing interaction of the ESS (grey) with the phosphotyrosine binding loop (reproduced with permission from Elsevier Press) [44]. Bottom panel: Amino acid alignment encompassing KIR, ESS and N-SH2 domain boundaries and highlighting residues critical for SOCS1 and SOCS3 function (*), residues conserved between SOCS1, 3, 4, 5 and Tkip (blue background), conserved between CIS, SOCS1-7 (green background), or conserved between SOCS5 and Tkip (purple font).