Find TNF Products Interaction Network for TNF TNF Details

Related Pathways Apoptosis Signaling Death Receptor Signaling Acute Phase Response Signaling View All Pathways

Synonyms: AT-TNF, DIF, Differentiation-induced Factor, MGC124630, MGC151434, RATTNF, TMTNF, TNF, TNF-ALPHA, TNFA, Tnfsf1a, TNFSF2

Apoptosis Through Death Receptors

Apoptosis is a normal cellular process involving physiologically relevant cell death. Apoptosis is initiated and promoted by a wide variety of intra- and extra-cellular stimuli. Extra-cellular induced apoptosis can be triggered by cell surface “death” receptors that possess cytoplasmic death domains (FADD, TRADD), typified by members of the tumor necrosis factor receptor superfamily: tumor necrosis factor (TNF) receptor 1 (TNFR-1), TNF-related apoptosis-inducing ligand receptor 1 (TRAILR-1), TRAILR-2, death receptor 3 (DR3/Wsl-1/APO-3/TRAMP/LARD), DR6, ectodermal dysplasia receptor (EDAR), p75-nerve growth factor receptor (p75-NGFR) and Fas/Apo-1/CD95 or by the action of the cytotoxic T-cell proteins such as granzyme-B and perforin.

Apoptotic events are propagated by members of a family of regulated proteolytic enzymes called caspases. The caspases most often associated with apoptosis are caspases 2, 3, 6, 7, 8, 9 and 10. Caspase cascades are composed of upstream (initiator) caspases (2, 8, 10), which are activated by death receptor signalosomes (DISC); caspase 9, which is activated by the mitochondrial cytochrome C/Apaf-1 derived apoptosome; and downstream (effector) caspases (3, 6, 7) that cleave proteins involved in programmed cell death events.

Caspase 2, caspase 8 and caspase 10 are activated through interaction with death receptor cytoplasmic death-inducing signaling complexes (DISC)) that contain FAS-associating death domain (FADD) or TNFR1-associated death domain (TRADD). These receptors are activated by ligands that are involved with signaling cell death to support cell selection, tissue homeostasis, morphogenesis, and host defense in multi-cellular organisms. Typical death receptor ligands include Fas ligand (FasL), tumor necrosis factor alpha (TNFα), NF-related apoptosis inducing ligand (TRAIL), TNF-related weak inducer of apoptosis TWEAK, TNF ligand-related molecule 1 (TL1A) and nerve growth factor (NGF).