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The signaling adaptors and pathways activated by TNF superfamily
Paul W Dempsey1, Sean E Doyle, Jeannie Q He
1Department of Microbiology, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, 8-240 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Abstract:
Members of the TNF receptor superfamily play pivotal roles in numerous biological events in metazoan organisms. Ligand-mediated trimerization by corresponding homo- or heterotrimeric ligands, the TNF family ligands, causes recruitment of several intracellular adaptors, which activate multiple signal transduction pathways. While recruitment of death domain (DD) containing adaptors such as Fas associated death domain (FADD) and TNFR associated DD (TRADD) can lead to the activation of a signal transduction pathway that induces apoptosis, recruitment of TRAF family proteins can lead to the activation of transcription factors such as, NF-kappaB and JNK thereby promoting cell survival and differentiation as well as immune and inflammatory responses. Individual TNF receptors are expressed in different cell types and have a range of affinities for various intracellular adaptors, which provide tremendous signaling and biological specificities. In addition, numerous signaling modulators are involved in regulating activities of signal transduction pathways downstream of receptors in this superfamily. Most of the TNF receptor superfamily members as well as many of their signaling mediators, have been uncovered in the last two decades. However, much remains unknown about how individual signal transduction pathways are regulated upon activation by any particular TNF receptor, under physiological conditions.
Insights
Members of the Tumor Necrosis Factor (TNF) receptor superfamily are crucial for biological events. Their signaling pathways, involving adaptors like FADD and TRAF proteins, regulate cell death, survival, and immune responses, but precise physiological regulation remains unclear.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- The Tumor Necrosis Factor (TNF) receptor superfamily is vital for metazoan biological processes.
- Ligand binding induces receptor trimerization, recruiting intracellular adaptors to activate signaling pathways.
Purpose of the Study:
- To elucidate the complex signaling mechanisms downstream of TNF receptors.
- To understand how TNF receptor superfamily members regulate diverse cellular functions.
Main Methods:
- The study reviews existing literature on TNF receptor signaling pathways.
- Analysis of adaptor protein recruitment (e.g., FADD, TRADD, TRAF) and downstream transcription factor activation (e.g., NF-kappaB, JNK).
Main Results:
- Recruitment of death domain (DD) adaptors like FADD and TRADD can trigger apoptosis.
- Recruitment of TRAF proteins activates pathways promoting cell survival, differentiation, and immune responses.
Conclusions:
- TNF receptor signaling exhibits specificity through differential adaptor binding and expression patterns.
- Despite recent discoveries, the precise physiological regulation of these pathways remains an area requiring further investigation.