Research ArticleImmunology

Dephosphorylation of the adaptor LAT and phospholipase C–γ by SHP-1 inhibits natural killer cell cytotoxicity

Sci. Signal.  24 May 2016:
Vol. 9, Issue 429, pp. ra54
DOI: 10.1126/scisignal.aad6182

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Keeping NK cells in check

Natural killer (NK) cells are immune cells that recognize and kill virally infected cells and tumor cells. Whether an NK cell becomes activated or inhibited depends on the relative extent of signaling by cell surface activating or inhibitory receptors that are engaged. Inhibitory receptor signaling activates the inhibitory phosphatase SHP-1. In experiments with human NK cells, Matalon et al. identified the adaptor protein LAT and two members of the phospholipase C–γ family as substrates of SHP-1. Inhibitory receptor signaling not only resulted in dephosphorylation of LAT, which reduced intracellular Ca2+ signaling by activating receptors, but also promoted LAT ubiquitylation and degradation, further dampening NK cell function.

Abstract

Natural killer (NK) cells discriminate between healthy cells and virally infected or transformed self-cells by tuning activating and inhibitory signals received through cell surface receptors. Inhibitory receptors inhibit NK cell function by recruiting and activating the tyrosine phosphatase Src homology 2 (SH2) domain–containing protein tyrosine phosphatase–1 (SHP-1) to the plasma membrane. However, to date, the guanine nucleotide exchange factor VAV1 is the only direct SHP-1 substrate identified in NK cells. We reveal that the adaptor protein linker for activation of T cells (LAT) as well as phospholipase C–γ1 (PLC-γ1) and PLC-γ2 are SHP-1 substrates. Dephosphorylation of Tyr132 in LAT by SHP-1 in NK cells abrogated the recruitment of PLC-γ1 and PLC-γ2 to the immunological synapse between the NK cell and a cancer cell target, which reduced NK cell degranulation and target cell killing. Furthermore, the ubiquitylation of LAT by the E3 ubiquitin ligases c-Cbl and Cbl-b, which was induced by LAT phosphorylation, led to the degradation of LAT in response to the engagement of inhibitory receptors on NK cells, which abrogated NK cell cytotoxicity. Knockdown of the Cbl proteins blocked LAT ubiquitylation, which promoted NK cell function. Expression of a ubiquitylation-resistant mutant LAT blocked inhibitory receptor signaling, enabling cells to become activated. Together, these data identify previously uncharacterized SHP-1 substrates and inhibitory mechanisms that determine the response of NK cells.

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