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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1 June 1998
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June 01 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
Sheng Wei,
Sheng Wei
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
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Ana M. Gamero,
Ana M. Gamero
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
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Jin Hong Liu,
Jin Hong Liu
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
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Angela A. Daulton,
Angela A. Daulton
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
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Nichola I. Valkov,
Nichola I. Valkov
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
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Joseph A. Trapani,
Joseph A. Trapani
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
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Andrew C. Larner,
Andrew C. Larner
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
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Michael J. Weber,
Michael J. Weber
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
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Julie Y. Djeu
Julie Y. Djeu
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
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Sheng Wei
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
Ana M. Gamero
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
Jin Hong Liu
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
Angela A. Daulton
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
Nichola I. Valkov
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
Joseph A. Trapani
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
Andrew C. Larner
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
Michael J. Weber
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
Julie Y. Djeu
From the *Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, Department of Biochemistry and Molecular Biology, Tampa, Florida 33612; the ‡Cellular Cytotoxicity Laboratory, Austin Research Institute, Heidelberg, Victoria 3084, Australia; the §Department of Immunology, Cleveland Clinic Research Foundation, Cleveland, Ohio 44195; and the ‖Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908
Address correspondence to Julie Y. Djeu, Program Leader, Immunology Program, H. Lee Moffitt Cancer Center, University of South Florida College of Medicine, 12902 Magnolia Dr., Tampa, FL 33612. Phone: 813-979-3041; Fax: 813-979-7264; E-mail: [email protected]
Received:
July 30 1997
Revision Received:
March 27 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 187 (11): 1753–1765.
Article history
Received:
July 30 1997
Revision Received:
March 27 1998
Citation
Sheng Wei, Ana M. Gamero, Jin Hong Liu, Angela A. Daulton, Nichola I. Valkov, Joseph A. Trapani, Andrew C. Larner, Michael J. Weber, Julie Y. Djeu; 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 . J Exp Med 1 June 1998; 187 (11): 1753–1765. doi: https://doi.org/10.1084/jem.187.11.1753
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