Inhibition of the phosphatase SHP-1 by PKC-θ maintains the NK cell activation threshold and cytotoxic capacity

Natural Killer (NK) cells are vital components of the immune system, tasked with eliminating virally infected and cancerous cells. Their activity is tightly regulated by a balance of activating and inhibitory receptor signals. However, the precise molecular mechanisms that enable NK cells to distinguish between healthy and malignant cells in complex tissue environments remain incompletely defined. The SHP-1 tyrosine phosphatase is the central negative NK cell regulator, which dephosphorylates key activating signaling proteins. Though the mechanism by which SHP-1 mediates NK cell inhibition has been partially elucidated, the pathways by which SHP-1 is itself regulated remain unclear. Our findings identify phosphorylation of SHP-1 at the S591 residue by PKC-θ as a critical regulatory event that stabilizes its inactive "folded" conformation. Disruption of PKC-θ activity shifts SHP-1 toward an active state, suppressing NK cell activation and cytotoxic function, ultimately facilitating tumor progression in vivo. These insights uncover a previously unrecognized pathway that fine-tunes NK cell responsiveness by modulating SHP-1 activity, offering potential targets for therapeutic intervention.

This research was recently published in eLife 11:e73282, 2022. doi: 10.7554/eLife.73282.