Inhibition of the SHP-1 activity by PKC-θ regulates NK cell activation threshold and cytotoxicity

Abstract

Natural Killer (NK) cells play a crucial role in immunity, killing virally infected and cancerous cells. The balance of signals initiated upon engagement of activating and inhibitory NK receptors with cognate ligands determines killing or tolerance. Nevertheless, the molecular mechanisms regulating rapid NK cell discrimination between healthy and malignant cells in a heterogeneous tissue environment are incompletely understood. 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. Here, we show that phosphorylation of SHP-1 in NK cells on the S591 residue by PKC-θ promotes the inhibited SHP-1 "folded" state. Silencing PKC-θ maintains SHP-1 in the active conformation, reduces NK cell activation and cytotoxicity, and promotes tumor progression in-vivo. This study reveals a molecular pathway that sustains the NK cell activation threshold through suppression of SHP-1 activity.

Unleashing Anti-Tumor Activity of Natural Killer Cells Via Modulation of Immune Checkpoints Receptors and Molecules

“…Ben-Shmuel et al demonstrated that protein kinase c theta (PKC-θ) phosphorylates the S591 residue of SHP-1, maintaining SHP-1 in the inactivated, "dormant" state [37]. Accordingly, silencing PKC-θ reactivates SHP-1, consequently reducing NK cell cytotoxicity and promoting cancer progression [37]. These results reinforced the tumor-suppressive impact of blocking SHP-1 activity.…”

“…Even though the strategy employed by SHP-1 to negatively regulate NK cell activation has been investigated for a relatively long period of time, it was not until very recently that how the regulatory pathway of SHP-1 itself was discovered. Ben-Shmuel et al demonstrated that protein kinase c theta (PKC-θ) phosphorylates the S591 residue of SHP-1, maintaining SHP-1 in the inactivated, "dormant" state [37]. Accordingly, silencing PKC-θ reactivates SHP-1, consequently reducing NK cell cytotoxicity and promoting cancer progression [37].…”