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    Control of lytic function by mitogen-activated protein kinase extracellular regulatory kinase 2 (ERK2) in a human natural killer cell line: Identification of perforin and granzyme B mobilization by functional ERK2

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    Author
    Wei, S; Gamero, AM; Liu, JH; Daulton, AA; Valkov, NI; Trapani, JA; Larner, AC; Weber, MJ; Djeu, JY
    Date
    1998-06-01
    Source Title
    Journal of Experimental Medicine
    Publisher
    ROCKEFELLER UNIV PRESS
    University of Melbourne Author/s
    Trapani, Joseph
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Wei, S., Gamero, A. M., Liu, J. H., Daulton, A. A., Valkov, N. I., Trapani, J. A., Larner, A. C., Weber, M. J. & Djeu, J. Y. (1998). Control of lytic function by mitogen-activated protein kinase extracellular regulatory kinase 2 (ERK2) in a human natural killer cell line: Identification of perforin and granzyme B mobilization by functional ERK2. JOURNAL OF EXPERIMENTAL MEDICINE, 187 (11), pp.1753-1765. https://doi.org/10.1084/jem.187.11.1753.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257914
    DOI
    10.1084/jem.187.11.1753
    Abstract
    The signal pathways that control effector function in human natural killer (NK) cells are little known. In this study, we have identified the critical role of the mitogen-activated protein kinase (MAPK) pathway in NK lysis of tumor cells, and this pathway may involve the mobilization of granule components in NK cells upon interaction with sensitive tumor target cells. Evidence was provided by biological, biochemical, and gene transfection methods. NK cell binding to tumor cells for 5 min was sufficient to maximally activate MAPK/extracellular signal-regulatory kinase 2 (ERK2), demonstrated by its tyrosine phosphorylation and by its ability to function as an efficient kinase for myelin basic protein. MAPK activation was achieved in NK cells only after contact with NK-sensitive but not NK-resistant target cells. In immunocytochemical studies, cytoplasmic perforin and granzyme B were both maximally redirected towards the tumor contact zone within 5 min of NK cell contact with tumor cells. A specific MAPK pathway inhibitor, PD098059, could block not only MAPK activation but also redistribution of perforin/granzyme B in NK cells, which occur upon target ligation. PD098059 also interfered with NK lysis of tumor cells in a 5-h 51Cr-release assay, but had no ability to block NK cell proliferation. Transient transfection studies with wild-type and dominant-negative MAPK/ERK2 genes confirmed the importance of MAPK in NK cell lysis. These results document a pivotal role of MAPK in NK effector function, possibly by its control of movement of lytic granules, and clearly define MAPK involvement in a functional pathway unlinked to cell growth or differentiation.

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