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The TNF Pathway
The TNF Pathway
Summary of Pathway:
It is essential for a cell to regulate the way that it responds to external stress and stimuli. Damaged cells may respond to their environment in a multitude of ways, and when their vital functions have been substantially affected, one of these possible responses is the initiation of self-mediated cell death. This process is the result of a signaling cascade that begins when a small ligand called TNF (tumor necrosis factor) binds to its transmembrane receptor on a damaged cell’s plasma membrane. The activated receptor complex then recruits additional molecules within the cell to its intracellular domain, including RIPK1 and TRADD. RIPK1 is an essential protein in the pathway because it begins the process of determining whether the cell will undergo necroptosis (a form of cell death that does not involve caspases) or apoptosis (conventional programmed cell death). There are 3 other primary checkpoints in the pathway that are dependent on phosphorylation of downstream proteins, the ubiquitination of complex II, (which is activated by RIPK1), and a transcriptional checkpoint (where the level of transcription of “prosurvival genes” determines whether the cell death process will be inhibited or not). If the pathway continues, the levels of RIPK3 (which promotes necroptosis) and caspase 8 (necessary for apoptosis) control which death process will take place. Overall, the TNF pathway is capable of inducing cell death via these two methods, and creates an inflammatory response in the cell by upregulating a variety of other cytokines (proinflammatory molecules).
Key Functions of TNF Pathway
- Stimulation of Proinflammatory Response:
Although TNF signaling plays an essential role in initiating programmed cell death, one of its primary functions is to produce an inflammatory response in damaged cells. This occurs because the pathway causes the activation of the transcription factor NF-kb, which upregulates transcription of genes promoting cell survival and inflammatory responses to cell stress. Therefore, in cells where high levels of cell survival factors prevent programmed cell death from occurring, a severe inflammatory reaction may occur.
