Inhibition of SHP-1 activity by PKC-θ regulates NK cell activation threshold and cytotoxicity.
PKC
SHP-1
cancer
human
immunology
inflammation
natural killer
signaling
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
08 03 2022
08 03 2022
Historique:
received:
23
08
2021
accepted:
23
02
2022
entrez:
8
3
2022
pubmed:
9
3
2022
medline:
30
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35258455
doi: 10.7554/eLife.73282
pii: 73282
pmc: PMC8903836
doi:
pii:
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
Protein Kinase C-theta
EC 2.7.11.13
PTPN6 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 6
EC 3.1.3.48
Protein Tyrosine Phosphatases
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2022, Ben-Shmuel et al.
Déclaration de conflit d'intérêts
AB, BS, AP, GB, ML, TJ, FA, RR, NJ, OM, JK, MB No competing interests declared
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