Integration of Activating and Inhibitory Receptor Signaling by Regulated Phosphorylation of Vav1 in Immune Cells

Sci. Signal.  31 May 2011:
Vol. 4, Issue 175, pp. ra36
DOI: 10.1126/scisignal.2001325

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Deciding Cytotoxicity

Natural killer (NK) cell activity depends on the interplay between activating and inhibitory receptors. Activating receptors stimulate the recruitment and phosphorylation of Vav1, a factor required to drive formation of the contact area between the NK cell and its target. Conversely, inhibitory receptor signaling results in the dephosphorylation of Vav1 to block activation. Mesecke et al. modeled multiple combinations of signaling events upstream of Vav1, classifying the input-output behaviors into different phenotypic classes. The authors used their models to predict that Vav1 occupied a central “decision-making” hub in the crosstalk between activating and inhibitory signals and that the phosphorylation of Vav1 depended on the physical association of activating receptors with Src family kinases. Further, the extent of phosphorylation of Vav1 correlated with the cytotoxic activity of NK cells. Validation of these predictions in NK cells suggests that this mathematical approach may prove useful in understanding the nonlinear integration of opposing signals in other systems.