Selective cross-talk among natural cytotoxicity receptors in human natural killer cells.
The cytolytic activity of human natural killer cells is induced by several triggering cell surface receptors upon interaction with specific cellular ligands. These receptors include NKp46, NKp30 and NKp44, collectively termed natural cytotoxicity receptors (NCR). Co-operation among NCR has been shown to occur for optimal recognition and killing of most tumor target cells. In this study, we show that the mAb-mediated engagement and clustering of one or another NCR results in the activation of an identical set of tyrosine kinases. These kinases are included in the signaling cascade leading to tyrosine phosphorylation of different receptor-associated signal transducing molecules i.e. CD3 zeta (associated with NKp46 and NKp30) and KARAP/DAP12 (associated with NKp44). In line with the notion that the engagement of inhibitory receptors prevents NCR-mediated responses, we show that the engagement of CD94/NKG2A virtually abrogates the tyrosine phosphorylation of the NCR-associated signaling molecules, i.e. it acts at the very early steps of the signaling cascade. Importantly, the engagement of a single NCR resulted in the activation of the signaling cascades associated with the other NCR. This "cross-talk" is confined to NKp46, NKp30 and NKp44 since neither CD16-nor KIR2DS4-associated signaling polypeptides were phosphorylated following the NCR engagement. These results suggest that a functional cross-talk specifically occurs among different NCR, possibly resulting in the amplification of the activating signals.
Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Raffaella
R
Augugliaro
Silvia
S
Parolini
Roberta
R
Castriconi
Emanuela
E
Marcenaro
Claudia
C
Cantoni
Marina
M
Nanni
Lorenzo
L
Moretta
Alessandro
A
Moretta
Cristina
C
Bottino
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD / Q000502:physiology; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051920:NK Cell Lectin-Like Receptor Subfamily D; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D055628:Natural Cytotoxicity Triggering Receptor 3; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism / Q000502:physiology*; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; C497869:KLRD1 protein, human; D037181:Lectins, C-Type; D008565:Membrane Proteins; C112260:NCR1 protein, human; C112837:NCR2 protein, human; C431710:NCR3 protein, human; D051920:NK Cell Lectin-Like Receptor Subfamily D; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D055628:Natural Cytotoxicity Triggering Receptor 3; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; C110546:TYROBP protein, human; C054979:antigen T cell receptor, zeta chain; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases