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* Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, Rome, Italy;
Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy; and
Istituto Mediterraneo di Neuroscienze Neuromed, Pozzilli, Italy
CD69 C-type lectin receptor represents a functional triggering
molecule on activated NK cells, capable of directing their natural
killing function. The receptor-proximal signaling pathways activated by
CD69 cross-linking and involved in CD69-mediated cytotoxic activity are
still poorly understood. Here we show that CD69 engagement leads to the
rapid and selective activation of the tyrosine kinase Syk, but not of
the closely related member of the same family, ZAP70, in IL-2-activated
human NK cells. Our results indicate the requirement for Src family
kinases in the CD69-triggered activation of Syk and suggest a role for
Lck in this event. We also demonstrate that Syk and Src family tyrosine
kinases control the CD69-triggered tyrosine phosphorylation and
activation of phospholipase C
2 and the Rho family-specific exchange
factor Vav1 and are responsible for CD69-triggered cytotoxicity of
activated NK cells. The same CD69-activated signaling pathways are also
observed in an RBL transfectant clone, constitutively expressing the
receptor. These data demonstrate for the first time that the CD69
receptor functionally couples to the activation of Src family tyrosine
kinases, which, by inducing Syk activation, initiate downstream
signaling pathways and regulate CD69-triggered functions on human NK
cells.
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