Figure 4

Attenuation of cytokine signaling. Suppressor of cytokinesignaling (SOCS) proteins are induced in response to cytokines and suppresssignal transduction in two ways. Some SOCS proteins bind directly to januskinases (Jaks) and inhibit their catalytic activity, whereas others likecytokine inducible src homology-2 protein (CIS) can bind to activatedreceptors and prevent docking by signaling intermediates such as the Stats.SHP-1 can either dephosphorylate Jaks or activated receptor subunits, dependingupon the pathway activated. Protein inhibitors of activated Stats (PIAS) familymembers inactivate Stat dimers by an as yet unknown mechanism. Stat dimers arealso probably downregulated by degradation and dephosphorylated by unknownmechanisms. The accumulation of STATs in the nucleus could be regulated at thelevel of nuclear import, nuclear export, or a combination of the two; themechanisms that control these processes are not well characterized. Finally,molecules like Bcl-6 can bind to consensus Stat binding sites and function asrepressors.