The Ability of SOCS1 to Cross-Regulate GM-CSF Signaling is Dose Dependent.

Suppressor of cytokine signaling (SOCS) 1 is a key negative regulator of interferon (IFN), interleukin (IL)12, and IL-2 family cytokine signaling through inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. To investigate the temporal induction of SOCS1 in response to cytokine in live cells and its selective regulation of signaling pathways, we generated a mouse expressing a Halo-tag-SOCS1 fusion protein (Halo-SOCS1) under control of the endogenous promoter. Homozygous Halo-SOCS1 mice () were viable with minor T cell abnormalities, most likely due to enhanced Halo-SOCS1 expression in thymocytes compared with the untagged protein.

CD45 limits early Natural Killer cell development.

The clinical development of Natural Killer (NK) cell-mediated immunotherapy marks a milestone in the development of new cancer therapies and has gained traction due to the intrinsic ability of the NK cell to target and kill tumor cells. To fully harness the tumor killing ability of NK cells, we need to improve NK cell persistence and to overcome suppression of NK cell activation in the tumor microenvironment. The trans-membrane, protein tyrosine phosphatase CD45, regulates NK cell homeostasis, with the genetic loss of CD45 in mice resulting in increased numbers of mature NK cells.

The SOCS1 KIR and SH2 domain are both required for suppression of cytokine signaling in vivo.

Suppressor Of Cytokine Signaling (SOCS) 1 is a critical negative regulator of cytokine signaling and required to protect against an excessive inflammatory response. Genetic deletion of Socs1 results in unrestrained cytokine signaling and neonatal lethality, characterised by an inflammatory immune infiltrate in multiple organs. Overexpression and structural studies have suggested that the SOCS1 kinase inhibitory region (KIR) and Src homology 2 (SH2) domain are important for interaction with and inhibition of the receptor-associated JAK1, JAK2 and TYK2 tyrosine kinases, which initiate downstream signaling.

Design and characterization of a heterobifunctional degrader of KEAP1.

The Kelch-like ECH-associated protein 1 (KEAP1) - nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway senses reactive oxygen species and regulates cellular oxidative stress. Inhibiting KEAP1 to activate the NRF2 antioxidant response has been proposed as a promising strategy to treat chronic diseases caused by oxidative stress. Here, we developed a proteolysis targeting chimera (PROTAC) that depletes KEAP1 from cells through the ubiquitin-proteasome pathway.

SOCS2 regulation of growth hormone signaling requires a canonical interaction with phosphotyrosine.

Suppressor of cytokine signaling (SOCS) 2 is the critical negative regulator of growth hormone (GH) and prolactin signaling. Mice lacking SOCS2 display gigantism with increased body weight and length, and an enhanced response to GH treatment. Here, we characterized mice carrying a germ-line R96C mutation within the SOCS2-SH2 domain, which disrupts the ability of SOCS2 to interact with tyrosine-phosphorylated targets.

Determining Activation Status of Natural Killer Cells Following Stimulation via Cytokines and Surface Receptors.

Stimulation of Natural Killer (NK) cells with cytokines, target cell interaction, or antibody mediated activation of receptors on the NK cell surface enables the dissection of specific signaling intermediates in different activation pathways. NK cell activation status is commonly measured by production of interferon gamma (IFNγ) and expression of the degranulation marker LAMP-1 (CD107a). Cytotoxic potency can also be assessed by the production of perforin, granzymes, and tumor necrosis factor alpha (TNFα).

CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8 T Cells.

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8 TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226 TILs were highly functional.

Natural Killer Cells: Tumor Surveillance and Signaling.

Natural killer (NK) cells play a pivotal role in cancer immunotherapy due to their innate ability to detect and kill tumorigenic cells. The decision to kill is determined by the expression of a myriad of activating and inhibitory receptors on the NK cell surface. Cell-to-cell engagement results in either self-tolerance or a cytotoxic response, governed by a fine balance between the signaling cascades downstream of the activating and inhibitory receptors.