Direct tumor lysis by NK cells uses a Ras-independent mitogen-activated protein kinase signal pathway

S. Wei, D. L. Gilvary, B. C. Corliss, S. Sebti, J. Sun, D. B. Straus, P. J. Leibson, J. A. Trapani, Andrew Hamilton, M. J. Weber, J. Y. Djeu

Research output: Contribution to journalArticle

Abstract

Destruction of tumor cells is a key function of lymphocytes, but the molecular processes driving it are unclear. Analysis of signal molecules indicated that mitogen-activated protein kinase (MAPK)/extracellular regulated kinase 2 critically controlled lytic function in human NK cells. We now have evidence to indicate that target ligation triggers a Ras-independent MAPK pathway that is required for lysis of the ligated tumor cell. Target engagement caused NK cells to rapidly activate MAPK within 5 min, and PD098059 effectively blocked both MAPK activation and tumoricidal function in NK cells. Target engagement also rapidly activated Ras, detected as active Ras-GTP bound to GST-Raf-RBD, a GST fusion protein linked to the Raf protein fragment containing the Ras-GTP binding domain. However, Ras inactivation by pharmacological disruption with the farnesyl transferase inhibitor, FTI-277, had no adverse effect on the ability of NK cells to lyse tumor cells or to express MAPK activation upon target conjugation. Notably, MAPK inactivation with PD098059, but not Ras inactivation with FTI-277, could interfere with perforin and granzyme B polarization within NK cells toward the contacted target cell. using vaccinia delivery of N17 Ras into NK cells, we demonstrated that IL-2 activated a Ras-dependent MAPK pathway, while target ligation used a Ras-independent MAPK pathway to trigger lysis in NK cells.

Original languageEnglish (US)
Pages (from-to)3811-3819
Number of pages9
JournalJournal of Immunology
Volume165
Issue number7
StatePublished - Oct 1 2000

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Mitogen-Activated Protein Kinases
Natural Killer Cells
Signal Transduction
Neoplasms
Guanosine Triphosphate
Ligation
Vaccinia
Transferases
Interleukin-2
Proteins
Phosphotransferases
Pharmacology
Lymphocytes

ASJC Scopus subject areas

  • Immunology

Cite this

Wei, S., Gilvary, D. L., Corliss, B. C., Sebti, S., Sun, J., Straus, D. B., ... Djeu, J. Y. (2000). Direct tumor lysis by NK cells uses a Ras-independent mitogen-activated protein kinase signal pathway. Journal of Immunology, 165(7), 3811-3819.

Direct tumor lysis by NK cells uses a Ras-independent mitogen-activated protein kinase signal pathway. / Wei, S.; Gilvary, D. L.; Corliss, B. C.; Sebti, S.; Sun, J.; Straus, D. B.; Leibson, P. J.; Trapani, J. A.; Hamilton, Andrew; Weber, M. J.; Djeu, J. Y.

In: Journal of Immunology, Vol. 165, No. 7, 01.10.2000, p. 3811-3819.

Research output: Contribution to journalArticle

Wei, S, Gilvary, DL, Corliss, BC, Sebti, S, Sun, J, Straus, DB, Leibson, PJ, Trapani, JA, Hamilton, A, Weber, MJ & Djeu, JY 2000, 'Direct tumor lysis by NK cells uses a Ras-independent mitogen-activated protein kinase signal pathway', Journal of Immunology, vol. 165, no. 7, pp. 3811-3819.
Wei S, Gilvary DL, Corliss BC, Sebti S, Sun J, Straus DB et al. Direct tumor lysis by NK cells uses a Ras-independent mitogen-activated protein kinase signal pathway. Journal of Immunology. 2000 Oct 1;165(7):3811-3819.
Wei, S. ; Gilvary, D. L. ; Corliss, B. C. ; Sebti, S. ; Sun, J. ; Straus, D. B. ; Leibson, P. J. ; Trapani, J. A. ; Hamilton, Andrew ; Weber, M. J. ; Djeu, J. Y. / Direct tumor lysis by NK cells uses a Ras-independent mitogen-activated protein kinase signal pathway. In: Journal of Immunology. 2000 ; Vol. 165, No. 7. pp. 3811-3819.
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