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Syk Regulation of Phosphoinositide 3-Kinase-Dependent NK Cell Function¹

Kun Jiang^2,*, Bin Zhong^2,*, Danielle L. Gilvary^*, Brian C. Corliss^*, Eric Vivier, Elizabeth Hong-Geller, Sheng Wei^* and Julie Y. Djeu^3,*

^* Immunology Program, H. Lee Moffitt Cancer Center, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, FL 33612; Center d’Immunologie Institut National de la Santé et de la Recherche Médicale/Centre National de la Recherche Scientifique de Marseille-Luminy, Marseille, France; and Biosciences Division, Los Alamos National Laboratory, Los Alamos, NM 87545

Emerging evidence suggests that NK-activatory receptors use KARAP/DAP12, CD3, and FcRI 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 PI3KRac1PAK1mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinaseERK 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 that Syk is upstream of all these signaling events. Confirming that Syk does not act downstream of PI3K, constitutively active PI3K reactivated all the downstream effectors as well as NK cytotoxicity suppressed in Syk-impaired NK cells. Our results are the first report documenting the instrumental role of Syk in control of PI3K-dependent natural cytotoxicity.

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