Type II tumour necrosis factor-alpha receptor (TNFR2) activates c-Jun N-terminal kinase (JNK) but not mitogen-activated protein kinase (MAPK) or p38 MAPK pathways

O. J. Jupp, Shona Moira McFarlane, H. M. Anderson, Alison Littlejohn, Ahmed Mohamed, R. H. MacKay, P. Vandenabeele, David Joseph MacEwan

    Research output: Contribution to journalArticle

    51 Citations (Scopus)

    Abstract

    The pleitropic actions of tumour necrosis factor-a (TNF) are transmitted by the type 1 55 kDa TNF receptor (TNFR1) and type II 75 kDa TNF receptor (TNFR2), but the signalling mechanisms elicited by these two receptors are not fully understood. In the present study, we report for the first time subtype-specific differential kinase activation in cell models that respond to TNF by undergoing apoptotic cell death. KYM-1 human rhabdomyosarcoma cells and HeLa human cervical epithelial cells, engineered to overexpress TNFR2, displayed c-Jun N-terminal kinase (JNK) activation by wild-type TNF, a TNFR1-specific TNF mutant and a TNFR2-specific mutant TNF in combination with an agonistic TNFR2-specific monoclonal antiserum. A combination of the TNFR2-specific mutant and agonistic antiserum elicited maximal endogenous or exogenous TNFR2 responsiveness. Moreover, alternative expression of a TNFR2 deletion mutant lacking its cytoplasmic domain rendered the cells unable to activate JNK activity through this receptor subtype. The profile of JNK activation by TNFR1 was more transient than that of TNFR2, with TNFR2-induced JNK activity also being more sensitive to the caspase inhibitor, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone. Conversely, only activation of the TNFR1 could stimulate mitogen-activated protein kinase (MA-PK) or p38 MAPK activities in a time-dependent manner. The role of TNFR2 activation in enhanced apoptotic cell death was confirmed with agonistic monoclonal antisera in cells expressing high levels of TNFR2. Activation of TNFR2 alone elicited cell death, but full TNF-induced death required stimulation of both receptor types. These findings indicate that efficient activation of TNFR2 by soluble TNFs is achievable with co-stimulation by antisera, and that both receptors differentially modulate extracellular signal-regulated kinases contributing to the cytokine's cytotoxic response.

    Original languageEnglish
    Pages (from-to)525-535
    Number of pages10
    JournalBiochemical Journal
    Volume359
    Issue numberPt 3
    DOIs
    Publication statusPublished - 2001

    Keywords

    • apoptosis
    • cytokine receptors
    • protein kinases/phosphatases
    • signal transduction
    • KAPPA-B ACTIVATION
    • CELL-DEATH
    • HUMAN BETA(2)-ADRENOCEPTOR
    • SIGNAL-TRANSDUCTION
    • ENDOTHELIAL-CELLS
    • DISTINCT ROLES
    • UP-REGULATION
    • P55 RECEPTOR
    • PC60 CELLS
    • DUAL ROLE

    Cite this

    Type II tumour necrosis factor-alpha receptor (TNFR2) activates c-Jun N-terminal kinase (JNK) but not mitogen-activated protein kinase (MAPK) or p38 MAPK pathways. / Jupp, O. J.; McFarlane, Shona Moira; Anderson, H. M.; Littlejohn, Alison; Mohamed, Ahmed; MacKay, R. H.; Vandenabeele, P.; MacEwan, David Joseph.

    In: Biochemical Journal, Vol. 359, No. Pt 3, 2001, p. 525-535.

    Research output: Contribution to journalArticle

    Jupp, OJ, McFarlane, SM, Anderson, HM, Littlejohn, A, Mohamed, A, MacKay, RH, Vandenabeele, P & MacEwan, DJ 2001, 'Type II tumour necrosis factor-alpha receptor (TNFR2) activates c-Jun N-terminal kinase (JNK) but not mitogen-activated protein kinase (MAPK) or p38 MAPK pathways', Biochemical Journal, vol. 359, no. Pt 3, pp. 525-535. https://doi.org/10.1042/0264-6021:3590525
    Jupp, O. J. ; McFarlane, Shona Moira ; Anderson, H. M. ; Littlejohn, Alison ; Mohamed, Ahmed ; MacKay, R. H. ; Vandenabeele, P. ; MacEwan, David Joseph. / Type II tumour necrosis factor-alpha receptor (TNFR2) activates c-Jun N-terminal kinase (JNK) but not mitogen-activated protein kinase (MAPK) or p38 MAPK pathways. In: Biochemical Journal. 2001 ; Vol. 359, No. Pt 3. pp. 525-535.
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    abstract = "The pleitropic actions of tumour necrosis factor-a (TNF) are transmitted by the type 1 55 kDa TNF receptor (TNFR1) and type II 75 kDa TNF receptor (TNFR2), but the signalling mechanisms elicited by these two receptors are not fully understood. In the present study, we report for the first time subtype-specific differential kinase activation in cell models that respond to TNF by undergoing apoptotic cell death. KYM-1 human rhabdomyosarcoma cells and HeLa human cervical epithelial cells, engineered to overexpress TNFR2, displayed c-Jun N-terminal kinase (JNK) activation by wild-type TNF, a TNFR1-specific TNF mutant and a TNFR2-specific mutant TNF in combination with an agonistic TNFR2-specific monoclonal antiserum. A combination of the TNFR2-specific mutant and agonistic antiserum elicited maximal endogenous or exogenous TNFR2 responsiveness. Moreover, alternative expression of a TNFR2 deletion mutant lacking its cytoplasmic domain rendered the cells unable to activate JNK activity through this receptor subtype. The profile of JNK activation by TNFR1 was more transient than that of TNFR2, with TNFR2-induced JNK activity also being more sensitive to the caspase inhibitor, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone. Conversely, only activation of the TNFR1 could stimulate mitogen-activated protein kinase (MA-PK) or p38 MAPK activities in a time-dependent manner. The role of TNFR2 activation in enhanced apoptotic cell death was confirmed with agonistic monoclonal antisera in cells expressing high levels of TNFR2. Activation of TNFR2 alone elicited cell death, but full TNF-induced death required stimulation of both receptor types. These findings indicate that efficient activation of TNFR2 by soluble TNFs is achievable with co-stimulation by antisera, and that both receptors differentially modulate extracellular signal-regulated kinases contributing to the cytokine's cytotoxic response.",
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    AU - Jupp, O. J.

    AU - McFarlane, Shona Moira

    AU - Anderson, H. M.

    AU - Littlejohn, Alison

    AU - Mohamed, Ahmed

    AU - MacKay, R. H.

    AU - Vandenabeele, P.

    AU - MacEwan, David Joseph

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    AB - The pleitropic actions of tumour necrosis factor-a (TNF) are transmitted by the type 1 55 kDa TNF receptor (TNFR1) and type II 75 kDa TNF receptor (TNFR2), but the signalling mechanisms elicited by these two receptors are not fully understood. In the present study, we report for the first time subtype-specific differential kinase activation in cell models that respond to TNF by undergoing apoptotic cell death. KYM-1 human rhabdomyosarcoma cells and HeLa human cervical epithelial cells, engineered to overexpress TNFR2, displayed c-Jun N-terminal kinase (JNK) activation by wild-type TNF, a TNFR1-specific TNF mutant and a TNFR2-specific mutant TNF in combination with an agonistic TNFR2-specific monoclonal antiserum. A combination of the TNFR2-specific mutant and agonistic antiserum elicited maximal endogenous or exogenous TNFR2 responsiveness. Moreover, alternative expression of a TNFR2 deletion mutant lacking its cytoplasmic domain rendered the cells unable to activate JNK activity through this receptor subtype. The profile of JNK activation by TNFR1 was more transient than that of TNFR2, with TNFR2-induced JNK activity also being more sensitive to the caspase inhibitor, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone. Conversely, only activation of the TNFR1 could stimulate mitogen-activated protein kinase (MA-PK) or p38 MAPK activities in a time-dependent manner. The role of TNFR2 activation in enhanced apoptotic cell death was confirmed with agonistic monoclonal antisera in cells expressing high levels of TNFR2. Activation of TNFR2 alone elicited cell death, but full TNF-induced death required stimulation of both receptor types. These findings indicate that efficient activation of TNFR2 by soluble TNFs is achievable with co-stimulation by antisera, and that both receptors differentially modulate extracellular signal-regulated kinases contributing to the cytokine's cytotoxic response.

    KW - apoptosis

    KW - cytokine receptors

    KW - protein kinases/phosphatases

    KW - signal transduction

    KW - KAPPA-B ACTIVATION

    KW - CELL-DEATH

    KW - HUMAN BETA(2)-ADRENOCEPTOR

    KW - SIGNAL-TRANSDUCTION

    KW - ENDOTHELIAL-CELLS

    KW - DISTINCT ROLES

    KW - UP-REGULATION

    KW - P55 RECEPTOR

    KW - PC60 CELLS

    KW - DUAL ROLE

    U2 - 10.1042/0264-6021:3590525

    DO - 10.1042/0264-6021:3590525

    M3 - Article

    VL - 359

    SP - 525

    EP - 535

    JO - Biochemical Journal

    JF - Biochemical Journal

    SN - 0264-6021

    IS - Pt 3

    ER -