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Necroptosis is a form of regulated necrosis that is dependent on receptor interacting serine/threonine kinase 1 (RIP1), RIP3, and its substrate, mixed lineage kinase domain like pseudokinase (MLKL). Necroptosis occurs as a result of disturbances of the intracellular or extracellular microenvironment which are detected by death receptors such as TNFR1.
|Cat. No.||Product Name / Activity|
|Potent and selective receptor activating protein kinase 3 (RIP3) inhibitor; necroptosis inhibitor|
|RIP1 kinase inhibitor; inhibits necroptosis|
|Necroptosis inhibitor; also inhibits pyroptosis|
|Potent RIP1 kinase inhibitor; inhibits necroptosis|
Necroptosis is initiated by activation of TNFR1, which induces the formation of a complex (complex I), comprising the TNFR-associated death protein (TRADD) and RIP1 kinase. Deubiquitination of RIP1 enables its release from complex I, which then forms a complex with RIP3, known as the necrosome. The assembly of the necrosome is dependent on caspase 8 inactivation and the release of RIP1 from complex I. Active RIP3 then catalyzes the phosphorylation of MLKL leading to oligomerization of MLKL; these oligomers then translocate to the plasma membrane triggering membrane permeabilization. The mechanism by which MLKL triggers necroptosis is not fully understood. Necroptosis may also be initiated by other death receptors, such as fas (first apoptosis signal), interferons, toll-like receptors and Z-DNA-binding protein 1 (ZBP1).
Evidence suggests a proinflammatory role for necroptosis. One mechanism by which this is thought to occur is that dying cells may trigger the release of damage-associated molecular patterns (DAMPs), although further evidence is required to support this theory. Necroptosis may also induce disruption of epithelial barriers allowing pathogens to enter and trigger an immune response. Necroptotic cells are detected and removed by phagocytes. Necroptosis is thought to have a role in a range of inflammatory conditions, such as inflammatory bowel disease, steatohepatitis and psoriasis.
Tocris offers the following scientific literature for Necroptosis to showcase our products. We invite you to request* your copy today!
*Please note that Tocris will only send literature to established scientific business / institute addresses.
There are two currently recognized forms of programmed cell death: apoptosis and necroptosis. This poster summarizes the signaling pathways involved in apoptosis, necroptosis and cell survival following death receptor activation, and highlights the influence of the molecular switch, cFLIP, on cell fate.