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Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway
G Natoli1, A Costanzo, A Ianni
1Fondazione Andrea Cesalpino and Istituto di I Clinica Medica, Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy.
Abstract:
Interaction of the p55 tumor necrosis factor receptor 1 (TNF-R1)-associated signal transducer TRADD with FADD signals apoptosis, whereas the TNF receptor-associated factor 2 protein (TRAF2) is required for activation of the nuclear transcription factor nuclear factor kappa B. TNF-induced activation of the stress-activated protein kinase (SAPK) was shown to occur through a noncytotoxic TRAF2-dependent pathway. TRAF2 was both sufficient and necessary for activation of SAPK by TNF-R1; conversely, expression of a dominant-negative FADD mutant, which blocks apoptosis, did not interfere with SAPK activation. Therefore, SAPK activation occurs through a pathway that is not required for TNF-R1-induced apoptosis.
Insights
Tumor necrosis factor receptor 1 (TNF-R1) signaling activates stress-activated protein kinase (SAPK) via TRAF2, independent of apoptosis signaling through FADD. This pathway highlights distinct TNF-R1 signaling routes.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Immunology
Background:
- Tumor necrosis factor receptor 1 (TNF-R1) mediates crucial cellular responses, including apoptosis and inflammation.
- Distinct adaptor proteins, TRADD and FADD, are involved in TNF-R1 signaling, with TRADD-FADD mediating apoptosis.
- TNF receptor-associated factor 2 (TRAF2) is implicated in nuclear factor kappa B activation.
Purpose of the Study:
- To elucidate the specific pathways involved in TNF-R1-induced stress-activated protein kinase (SAPK) activation.
- To determine the role of TRAF2 and FADD in TNF-R1 signaling to SAPK.
- To investigate whether SAPK activation is a prerequisite for TNF-R1-mediated apoptosis.
Main Methods:
- Utilized dominant-negative FADD mutants to block apoptosis.
- Assessed SAPK activation in response to TNF-R1 stimulation.
- Investigated the necessity and sufficiency of TRAF2 for SAPK activation.
Main Results:
- TNF-R1-induced SAPK activation occurs through a TRAF2-dependent pathway.
- TRAF2 is both sufficient and necessary for TNF-R1-mediated SAPK activation.
- Inhibition of apoptosis by a dominant-negative FADD mutant did not affect SAPK activation.
Conclusions:
- SAPK activation by TNF-R1 is mediated by a TRAF2-dependent pathway.
- This SAPK activation pathway is distinct from and not required for TNF-R1-induced apoptosis.
- TNF-R1 signaling diverges into separate pathways for apoptosis and SAPK activation.