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Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells

Nature Immunology volume 1, pages 419425 (2000) | Download Citation

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  • An Erratum to this article was published on 01 December 2000

Abstract

The mitogen-activated protein kinase–extracellular signal–regulated kinase signaling element (MAPK-ERK) plays a critical role in natural killer (NK) cell lysis of tumor cells, but its upstream effectors were previously unknown. We show that inhibition of phosphoinositide-3 kinase (PI3K) in NK cells blocks p21-activated kinase 1 (PAK1), MAPK kinase (MEK) and ERK activation by target cell ligation, interferes with perforin and granzyme B movement toward target cells and suppresses NK cytotoxicity. Dominant-negative N17Rac1 and PAK1 mimic the suppressive effects of PI3K inhibitors, whereas constitutively active V12Rac1 has the opposite effect. V12Rac1 restores the activity of downstream effectors and lytic function in LY294002- or wortmannin-treated, but not PD98059-treated, NK cells. These results document a specific PI3K→Rac1→PAK1→MEK→ERK pathway in NK cells that effects lysis.

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Acknowledgements

We thank the Analytical Microscopy Core and the Molecular Imaging Core facilities of the H. Lee Moffitt Cancer and R. Buettner for comments on the manuscript. Supported by the US Public Health Service (CA83146) and American Heart Association (AHA9701715).

Author information

Affiliations

  1. Immunology Program, H. Lee Moffitt Cancer Center, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, FL 33612, USA.

    • Kun Jiang
    • , Bin Zhong
    • , Danielle L. Gilvary
    • , Brian C. Corliss
    • , Sheng Wei
    •  & Julie Y. Djeu
  2. Los Alamos National Laboratories, Los Alamos, NM 87545, USA.

    • Elizabeth Hong-Geller

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Correspondence to Julie Y. Djeu.

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DOI

https://doi.org/10.1038/80859

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