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The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, interleukin-12 and interleukin-2 family cytokines. These cytokines have a critical role in orchestrating our immune defence against viral pathogens and cancer. The ability of SOCS1 to limit cytokine signaling positions it as an important immune checkpoint, as evidenced by the detection of detrimental SOCS1 variants in patients with cytokine-driven inflammatory and autoimmune disease. SOCS1 has also emerged as a key checkpoint that restricts anti-tumor immunity, playing both a tumor intrinsic role and impacting the ability of various immune cells to mount an effective anti-tumor response. In this review, we describe the mechanism of SOCS1 action, focusing on the role of SOCS1 in autoimmunity and cancer, and discuss the potential for new SOCS1-directed cancer therapies that could be used to enhance adoptive immunotherapy and immune checkpoint blockade.

Abstract Protein Tyrosine Phosphatase 1B (PTP1B) is the prototypical protein tyrosine phosphatase and plays an essential role in the regulation of several kinase-driven signalling pathways. PTP1B displays a preference for bisphosphorylated substrates. Here we identify PTP1B as an inhibitor of IL-6 and show that, in vitro, it can dephosphorylate all four members of the JAK family. In order to gain a detailed understanding of the molecular mechanism of JAK dephosphorylation, we undertook a structural and biochemical analysis of the dephosphorylation reaction. We identified a product-trapping PTP1B mutant that allowed visualisation of the tyrosine and phosphate products of the reaction and a substrate-trapping mutant with a vastly decreased off-rate compared to those previously described. The latter mutant was used to determine the structure of bisphosphorylated JAK peptides bound to the enzyme active site. These structures revealed that the downstream phosphotyrosine preferentially engaged the active site, in contrast to the analogous region of IRK. Biochemical analysis confirmed this preference. In this binding mode, the previously identified second aryl binding site remains unoccupied and the non-substrate phosphotyrosine engages Arg47. Mutation of this arginine disrupts the preference for the downstream phosphotyrosine. This study reveals a previously unappreciated plasticity in how PTP1B interacts with different substrates.

Abstract Suppressor of cytokine signaling (SOCS)2 protein is a key negative regulator of the growth hormone (GH) and Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) signaling cascade. The central SOCS2-Src homology 2 (SH2) domain is characteristic of the SOCS family proteins and is an important module that facilitates recognition of targets bearing phosphorylated tyrosine (pTyr) residues. Here we identify an exosite on the SOCS2-SH2 domain which, when bound to a non-phosphorylated peptide (F3), enhances SH2 affinity for canonical phosphorylated ligands. Solution of the SOCS2/F3 crystal structure reveals F3 as an α-helix which binds on the opposite side of the SH2 domain to the phosphopeptide binding site. F3:exosite binding appears to stabilise the SOCS2-SH2 domain, resulting in slower dissociation of phosphorylated ligands and consequently, enhances binding affinity. This biophysical enhancement of SH2:pTyr binding affinity translates to increase SOCS2 inhibition of GH signaling.