Inhibition of Cytokine Signaling

The JAK-STAT pathway is turned off some time after signaling is activated. There are three classes of proteins that

Figure 4 Structure of STATs: (A) schematic diagram showing the domains of STAT1; (B) crystal structure of the core domain of STAT1 bound to DNA. Dimeric STATs form a C-shaped clamp around DNA that is stabilized by reciprocal interactions between the SH2 domain of one monomer and a phosphorylated tyrosine of the other. The phosphotyrosine-binding site of the SH2 domain in each monomer is coupled structurally to the DNA-binding domain, suggesting a potential role for the SH2-phosphotyrosine interaction in the stabilization of DNA interacting elements. (Part B from Chen, X. et al., Cell, 93, 827-839, 1998. With permission.)

Figure 4 Structure of STATs: (A) schematic diagram showing the domains of STAT1; (B) crystal structure of the core domain of STAT1 bound to DNA. Dimeric STATs form a C-shaped clamp around DNA that is stabilized by reciprocal interactions between the SH2 domain of one monomer and a phosphorylated tyrosine of the other. The phosphotyrosine-binding site of the SH2 domain in each monomer is coupled structurally to the DNA-binding domain, suggesting a potential role for the SH2-phosphotyrosine interaction in the stabilization of DNA interacting elements. (Part B from Chen, X. et al., Cell, 93, 827-839, 1998. With permission.)

deactivate cytokine signaling at a number of levels [35]. Because the entire cascade is dependent on tyrosine phosphorylation as an activation signal, dephosphorylation by tyrosine phosphatases is obviously an important regulatory step. Specifically, the SH2 domain containing protein tyrosine phosphatase, SHP-1, binds tyrosine-phosphorylated cytokine receptors, such as EpoR, via its SH2 domain and dephosphorylates JAK2 [36]. SHP-1 has also been shown to associate directly with and dephosphorylate JAK2, and this association is independent of the SH2 domain [37]. Tyrosine phosphatases are also implicated in the dephosphorylation and consequent inactivation of phosphorylated STAT molecules, although a specific phosphatase-STAT association has yet to be demonstrated [38].

Another class of proteins involved in switching off the JAK-STAT signal is the suppressor of cytokine signaling (SOCS) family of proteins [39]. SOCS proteins contain a central SH2 domain flanked by an N-terminal domain of variable length and sequence and a C-terminal region containing a conserved motif called the SOCS box [38]. SOCS proteins inactivate JAK-STAT signaling by different mechanisms; SOCS-1 (also known as STAT-induced STAT inhibitor [SSI-1] or JAK2 binding protein [JAB]) binds JAKs in their activation loop in a phosphorylation-dependent manner and blocks ATP binding to the kinase, thereby inhibiting any further kinase activity [40-42]. Another member of the SOCS family, CIS (cytokine-inducible, SH2-containing protein), directly binds phosphorylated tyrosine residues on the cytokine receptor, blocking STAT recruitment and phosphorylation [43]. Interestingly, as the name SSI-1 suggests, transcription of the SOCS genes is induced by cytokines, at least partially via STAT transcription factors, thereby forming a negative feedback loop. Recent studies have shown that the SOCS box interacts with components of the proteasome machinery, suggesting that binding of SOCS to the receptor-JAKs complex might target them for ubiqui-tination and degradation [44].

The third class of JAK-STAT negative regulators is the protein inhibitors of STAT (PIAS) family of proteins [35,45]. Unlike SOCS, PIAS proteins are expressed consti-tutively but associate with STATs only upon stimulation of the cell by cytokines. PIAS proteins bind activated STAT dimers and inhibit their DNA binding activity. It is thought that these proteins might buffer the concentration of active STAT dimers in the cell.

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