Research ArticleImmunology

Complementary Phosphorylation Sites in the Adaptor Protein SLP-76 Promote Synergistic Activation of Natural Killer Cells

Sci. Signal.  10 Jul 2012:
Vol. 5, Issue 232, pp. ra49
DOI: 10.1126/scisignal.2002754

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Converging on an Adaptor for Deadly Activation

Natural killer (NK) cells target and kill virally infected cells and tumor cells, and their activation depends on the integration of responses to activating and inhibitory cell-surface receptors. Even in the absence of inhibitory receptor signaling, stimulation of an individual activating receptor fails to activate NK cells because of cell-intrinsic inhibition of signaling. However, combined stimulation of particular pairs of activating receptors results in a synergistic response that crosses the threshold required for cellular activation. Kim and Long found that pairs of activating receptors that enabled human NK cell activation led to the phosphorylation of a pair of complementary tyrosine residues in the adaptor protein SLP-76, whereas combined stimulation of nonsynergistic receptors failed to phosphorylate both tyrosines. Phosphorylation of both residues in SLP-76 was required for downstream signaling that led to cytokine production and target cell killing. Thus, SLP-76 acts as a molecular checkpoint that controls the activation of NK cells.