Nature Immunology Jiang et al. elucidate this pathway almost from start to finish1. NK cells lyse target cells via spontaneous or antibody-dependent cytotoxicity (ADCC). In both cases, phosphorylation resulting from engagement of receptors involved in target cell recognition results in the activation of specific protein kinases (the primary kinases being Src family kinases and Syk2) that are central to NK cell functions, including granule release. Also, in both cases, pharmacological inhibition of members of the mitogen-activated protein kinase (MAPK) family, specifically extracellular signal-regulated kinase (ERK) and p38, or overexpression of nonfunctional, mutated forms of these kinases, inhibits granule redistribution and release after target cell binding. Several intermediate molecules in the pathway of MAPK activation have been identified, but the exact sequence in which these kinases influence each other’s activity had not been established. In this issue, Jiang et al. propose that the redistribution of lytic granules (as determined by the movement of perforin and granzymes) in primary NK cells during spontaneous cytotoxicity depends on the receptortriggered sequential recruitment and activation of a Rac1→ p21− activated kinase 1 (PAK1)→ MAPK kinase (MEK)→ ERK pathway that is activated in a Ras-independent nature immunology• volume 1 no 5• november 2000• http://immunol. nature. com