Syk regulation of phosphoinositide 3-kinase-dependent NK cell function

The Journal of Immunology : Official Journal of the American Association of Immunologists
Kun JiangJulie Y Djeu

Abstract

Emerging evidence suggests that NK-activatory receptors use KARAP/DAP12, CD3zeta, and FcepsilonRIgamma adaptors that contain immunoreceptor tyrosine-based activatory motifs to mediate NK direct lysis of tumor cells via Syk tyrosine kinase. NK cells may also use DAP10 to drive natural cytotoxicity through phosphoinositide 3-kinase (PI3K). In contrast to our recently identified PI3K pathway controlling NK cytotoxicity, the signaling mechanism by which Syk associates with downstream effectors to drive NK lytic function has not been clearly defined. In NK92 cells, which express DAP12 but little DAP10/NKG2D, we now show that Syk acts upstream of PI3K, subsequently leading to the specific signaling of the PI3K-->Rac1-->PAK1-->mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase-->ERK cascade that we earlier described. Tumor cell ligation stimulated DAP12 tyrosine phosphorylation and its association with Syk in NK92 cells; Syk tyrosine phosphorylation and activation were also observed. Inhibition of Syk function by kinase-deficient Syk or piceatannol blocked target cell-induced PI3K, Rac1, PAK1, mitogen-activated protein/ERK kinase, and ERK activation, perforin movement, as well as NK cytotoxicity, indicating t...Continue Reading

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