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Modulation of life and death by the TNF receptor superfamily
1Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Abstract:
The tumor necrosis factor receptor (TNFR) superfamily represents a growing family, with over 20 members having been identified thus far in mammalian cells. These proteins share significant homologies in their extracellular ligand binding domains and intracellular effector (death) domains. These receptors appear to transmit their signals via protein-protein interactions, which convey either a death or survival signal. Isolation and characterization of death domain containing proteins (TRADD, FADD/MORT-1, RIP), TRAF domain containing proteins (TRAF1-6) as well as new members and adaptor proteins such as DAXX have provided new insights to our understanding of signaling mechanisms associated with this family of receptors. While the death signals seem to be associated with the activation of both the caspase and JUN kinase pathways, the survival signals are mediated via the activation of the NF-kappaB pathway.
Insights
The tumor necrosis factor receptor (TNFR) superfamily, with over 20 members, transmits signals via protein interactions, influencing cell death or survival. Key proteins like TRADD, FADD, RIP, TRAFs, and DAXX elucidate these complex signaling pathways.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- The tumor necrosis factor receptor (TNFR) superfamily comprises over 20 identified members in mammalian cells.
- TNFRs possess homologous extracellular ligand-binding and intracellular effector (death) domains.
- Receptor signaling is mediated through protein-protein interactions, dictating either cell death or survival outcomes.
Purpose of the Study:
- To investigate the signaling mechanisms of the TNFR superfamily.
- To characterize novel proteins involved in TNFR signaling pathways.
- To understand the molecular basis of death and survival signals transmitted by TNFRs.
Main Methods:
- Isolation and characterization of death domain-containing proteins (TRADD, FADD/MORT-1, RIP).
- Identification and analysis of TRAF domain-containing proteins (TRAF1-6).
- Investigation of adaptor proteins such as DAXX in TNFR signaling.
Main Results:
- New insights into TNFR signaling mechanisms were gained through the characterization of identified proteins.
- Death signals are associated with the activation of caspase and JUN kinase pathways.
- Survival signals are mediated by the activation of the NF-kappaB pathway.
Conclusions:
- The TNFR superfamily utilizes distinct intracellular proteins to transmit opposing signals.
- Understanding these signaling pathways is crucial for deciphering cellular fate decisions.
- Further research into TNFR signaling can inform therapeutic strategies for diseases involving aberrant cell death or survival.