PT  - JOURNAL ARTICLE
AU  - Aviad Ben-Shmuel
AU  - Batel Sabag
AU  - Guy Biber
AU  - Abhishek Puthenveetil
AU  - Moria Levy
AU  - Tammir Jubany
AU  - Noah Joseph
AU  - Omri Matalon
AU  - Jessica Kivelevitz
AU  - Mira Barda-Saad
TI  - Inhibition of the SHP-1 activity by PKC-θ regulates NK cell activation threshold and cytotoxicity
AID  - 10.1101/2021.09.06.459131
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.09.06.459131
4099  - http://biorxiv.org/content/early/2021/09/06/2021.09.06.459131.short
4100  - http://biorxiv.org/content/early/2021/09/06/2021.09.06.459131.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.