Figure 7.

Regulation of cytokine signaling. (A) Schematic diagram showing regulators of cytokine signaling and where they act. (B) Domain architecture of the proteins indicated in A. (C) The primary negative feedback regulators of cytokine signaling are a subset of the SOCS (Suppressors of Cytokine Signaling) family, CIS, SOCS1, SOCS2, and SOCS3. These proteins function as the substrate recruitment modules of an E3 ubiquitin ligase (model structure shown in surface representation) and promote the ubiquitination and degradation of cytokine receptors and potentially other substrates. Substrates bind to the SH2 domain of SOCS proteins (red) and ubiquitin is transferred via an E2 ubiquitin‐conjugating enzyme that docks onto the RING‐domain protein Rbx2 (white). SOCS1 and SOCS3 (right) can also directly inhibit the JAK kinase domain by using their kinase inhibitory region (KIR) to block the substrate binding site of the kinase (PDB ID: http://firstglance.jmol.org/fg.htm?mol=6C7Y) (model of a substrate overlay shown inset). (D) Six tyrosine phosphatases have been shown to be important regulators of cytokine‐pathway activity, acting by dephosphorylating JAKs, STATs, or receptors. The structure of one of these, SHP1, has been solved in complex with the JAK activation loop of JAK2 (PDB ID: http://firstglance.jmol.org/fg.htm?mol=4GSO).