SCIENCE SIGNALING

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Science  08 Aug 2008:
Vol. 321, Issue 5890, pp. 747
DOI: 10.1126/science.321.5890.747c

Natural killer (NK) cells navigate to transformed or virus-infected cells and bind to them through integrins and NK receptors to form a lytic synapse. Both steps depend on the actin cytoskeleton, leading Butler et al. to investigate the role of HS1 (a homolog of the actin-binding protein cortactin) in NK cell-mediated cytolysis. When NK cells were exposed to target cells or to beads coated with ICAM-1 (a ligand of the β2 integrin LFA-1) and the NK receptor ligand ULBP, HS1 localized to the contact site and became phosphorylated on tyrosine. Experiments in which HS1 was knocked down and cells were transfected with HS1 mutants where one or both of two tyrosine residues were substituted with phenylalanine implicated HS1 phosphorylation in NK cell cytolytic activity. Adhesion to ICAM-1 stimulated phosphorylation of HS1 on Tyr397; further, Tyr397 was required for chemokine-dependent conversion of LFA-1 into a high-affinity state and for downstream recruitment of actin, the actin regulator WASp, and the guanine nucleotide exchange factor Vav1 to the lytic synapse. Although HS1 Tyr397 was not required for recruitment of the adaptor DAP10 to the NKG2D receptor, it was implicated in downstream signaling. In contrast, phosphorylation of HS1 Tyr378 was required for chemotaxis. Thus, HS1 appears to be critical to NK cell chemotaxis, formation of the lytic synapse, and cytolysis, and may act as a switch to enable NK cells to convert from a migratory mode to one in which they form a stable contact with a target cell. — EMA

Nat. Immunol. 9, 887 (2008).

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