Endogenous cellular key regulators, capable of negatively regulating JAK/STAT-mediated signal transduction, include suppressor of cytokine signaling (SOCS) proteins, protein tyrosine phosphatases (PTP) and protein inhibitor of activated STATs (PIAS). The family of SOCS proteins comprises eight members (cytokine-inducible SH2 domain-containing protein (CIS) and SOCS1-7). All members contain a central SH2 domain, an Nterminus of variable length and sequence and a C-terminal 40 amino-acid module called SOCS box [22] . The SOCS box is necessary for recruitment of the ubiquitin transferase system and for stabilization and/or degradation of SOCS proteins [23] [24] [25] . The N-terminus contains a kinase inhibitory region (KIR), which functions as pseudo substrate for the JAK [26] . SOCS-1 and SOCS-3 differ in their mode of action. For inhibition of the kinase activity of JAKs, SOCS-1 binds directly to the activation loop of JAKs [26] [27] [28] . In contrast, SOCS-3 first binds to the receptor [29, 30] .