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*
Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza,
Biotechnology Section, Institute for the Study and Cure of Tumors, and
Laboratory of Pathophysiology, Regina Elena Cancer Institute, Rome, Italy;
§
Istituto Mediterraneo di Neuroscienze Neuromed, Pozzilli, Italy; and
¶
Servicio de Inmunologia, Hospital de La Princesa, Madrid, Spain
The CD94/NKG2-A complex is the inhibitory receptor for the
nonclassical MHC class I molecule HLA-E on human NK cells. Here we
studied the molecular mechanisms underlying the inhibitory activity of
CD94/NKG2-A on NK cell functions by analyzing its interference on
CD16-initiated signaling pathways involved in the control of cytolytic
activity. Both tyrosine phosphorylation and activation of Syk kinase
together with tyrosine phosphorylation of CD16 receptor 
subunit are
markedly inhibited by the coengagement of CD94/NKG2-A complex. As a
downstream consequence, CD94/NKG2-A cross-linking impairs the
CD16-induced activation of extracellular regulated kinases (ERKs), a
pathway involved in NK cytotoxic function. The block of ERK activation
is exerted at an early, PTK-dependent stage in the events leading to
p21ras activation, as the CD16-induced tyrosine
phosphorylation of Shc adaptor protein and the formation of Shc/Grb-2
complex are abrogated by CD94/NKG2-A simultaneous engagement. Our
observations indicate that CD94/NKG2-A inhibits the CD16-triggered
activation of two signaling pathways involved in the cytotoxic activity
of NK cells. They thus provide molecular evidence to explain the
inhibitory function of CD94/NKG2-A receptor on NK effector
functions.
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