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Activating and inhibitory functions of DAP12

Abstract

When associated with different receptors, the signalling adaptor DAP12 has been shown to both potentiate and attenuate the activation of leukocytes. But how can a protein with a single signalling motif elicit qualitatively different cellular responses? We describe a model of DAP12 function, whereby the quality of the cellular response (activation or inhibition) is modulated by the avidity of the interaction between the DAP12-associated receptor and its ligand. This model extends from previous studies of inhibitory signalling mediated by other adaptors, such as the Fc-receptor γ-chain and CD3ζ, and provides a potential mechanism for the conflicting phenotypes observed in studies of DAP12-deficient mice.

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Figure 1: DAP12 signalling: proven and probable signalling effectors.
Figure 2: Low-avidity versus high-avidity ligation of DAP12-associated receptors.
Figure 3: DAP12-mediated inhibition of Toll-like receptor activation by PI3K and PLCγ.

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Correspondence to Marco Colonna.

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Marco Colonna has stock options in the company Bioxell, Milan, Italy.

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Turnbull, I., Colonna, M. Activating and inhibitory functions of DAP12. Nat Rev Immunol 7, 155–161 (2007). https://doi.org/10.1038/nri2014

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