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

Aviad Ben-Shmuel, Batel Sabag, Abhishek Puthenveetil, Guy Biber, Moria Levy, Tammir Jubany, Fatima Awwad, Roshan Kumar Roy, Noah Joseph, Omri Matalon, Jessica Kivelevitz, Mira Barda-Saad

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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 that 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.

Original languageEnglish
Article numbere73282
JournaleLife
Volume11
DOIs
StatePublished - 8 Mar 2022

Bibliographical note

Publisher Copyright:
‍© Ben-Shmuel et al.

Funding

This research was partially funded by by the United States–Israel Binational Science Foundation (2019211). The authors thank Danielle Keizer and Dr. Itay Lazar from Bar-Ilan University for their technical assistance. We also thank Dr. Michael Milyavsky and Dr. Adi Zipin-Roitman from Tel-Aviv university for generously providing the NOD-SCID IL2Rγnull (NSG) mice, Dr. Jennifer Benichou Israel Cohen from Bar-Ilan University for her help with the statistical analysis, Dr. Liron Miller and Dr. Natalie Landa from the blood bank and transfusion center of Sheba medical center, Israel, for their technical assistance. Bar-Ilan University United States–Israel Binational Science Foundation (2019211) Mira Barda-Saad The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. This research was partially funded by by the United States–Israel Binational Science Foundation (2019211). The authors thank Danielle Keizer and Dr. Itay Lazar from Bar-Ilan University for their technical assistance. We also thank Dr. Michael Milyavsky and Dr. Adi Zipin-Roitman from Tel-Aviv university for generously providing the NOD-SCID IL2Rγnull (NSG) mice, Dr. Jennifer Benichou Israel Cohen from Bar-Ilan University for her help with the statistical analysis, Dr. Liron Miller and Dr. Natalie Landa from the blood bank and transfusion center of Sheba medical center, Israel, for their technical assistance.

FundersFunder number
United States - Israel Binational Science Foundation
United States-Israel Binational Science Foundation2019211
transfusion center of Sheba medical center, Israel

    Fingerprint

    Dive into the research topics of 'Inhibition of SHP-1 activity by PKC-θ regulates NK cell activation threshold and cytotoxicity'. Together they form a unique fingerprint.

    Cite this