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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.

ABSTRACT: The pleitropic actions of tumour necrosis factor-alpha (TNF) are transmitted by the type I 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 (MAPK) 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.

SUBMITTER: Jupp OJ

PROVIDER: S-EPMC1222173 | biostudies-other | 2001 Nov

REPOSITORIES: biostudies-other

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Project description:BackgroundThe metacestode larval stage of the fox-tapeworm Echinococcus multilocularis causes alveolar echinococcosis by tumour-like growth within the liver of the intermediate host. Metacestode growth and development is stimulated by host-derived cytokines such as insulin, fibroblast growth factor, and epidermal growth factor via activation of cognate receptor tyrosine kinases expressed by the parasite. Little is known, however, concerning signal transmission to the parasite nucleus and cross-reaction with other parasite signalling systems.Methodology/principal findingsUsing bioinformatic approaches, cloning, and yeast two-hybrid analyses we identified a novel mitogen-activated kinase (MAPK) cascade module that consists of E. multilocularis orthologs of the tyrosine kinase receptor interactor Growth factor receptor-bound 2, EmGrb2, the MAPK kinase kinase EmMEKK1, a novel MAPK kinase, EmMKK3, and a close homolog to c-Jun N-terminal kinase (JNK), EmMPK3. Whole mount in situ hybridization analyses indicated that EmMEKK1 and EmMPK3 are both expressed in E. multilocularis germinative (stem) cells but also in differentiated or differentiating cells. Treatment with the known JNK inhibitor SP600125 led to a significantly reduced formation of metacestode vesicles from stem cells and to a specific reduction of proliferating stem cells in mature metacestode vesicles.Conclusions/significanceWe provide evidence for the expression of a MEKK1-JNK MAPK cascade module which, in mammals, is crucially involved in stress responses, cytoskeletal rearrangements, and apoptosis, in E. multilocularis stem cells. Inhibitor studies indicate an important role of JNK signalling in E. multilocularis stem cell survival and/or maintenance. Our data are relevant for molecular and cellular studies into crosstalk signalling mechanisms that govern Echinococcus stem cell function and introduce the JNK signalling cascade as a possible target of chemotherapeutics against echinococcosis.

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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.

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