name: necroptotic signaling pathway
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def: "A series of molecular signals which triggers the necroptotic death of a cell. The pathway starts with reception of a signal, is characterized by activation of receptor-interacting serine/threonine-protein kinase 1 and/or 3 (RIPK1/3, also called RIP1/3), and ends when the execution phase of necroptosis is triggered." [GOC:mtg_apoptosis, PMID:20823910]
comment: Gene products that may be annotated to this term include: 1) ligands such as TNF-alpha; 2) receptors such as TNFR (though care should be taken because TNF-alpha and TNFR may also be involved in non-necroptotic processes); 3) signaling molecules such as TNFR-associated death domain (TRADD), receptor-interacting protein kinase 1 (RIP1), cellular inhibitor of apoptosis 1 (cIAP1), cIAP2, TNFR-associated factor 2 (TRAF2) and TRAF5. Within the so-called complex I, RIP1 is polyubiquitinated by cIAPs, thereby providing a docking site for the recruitment of transforming growth factor beta (TGFbeta)-activated kinase 1 (TAK1), TAK1-binding protein 2 (TAB2) and TAB3 (which together deliver a pro-survival signal by activating the transcription factor NF-kB). In some pathophysiological and experimental settings, and in particular when caspase-8 is absent or when caspases are inhibited by pharmacological agents, cylindromatosis (CYLD)-deubiquitinated RIP1 engage in physical and functional interactions with its homolog RIP3, ultimately activating the execution of necrotic cell death. (The pathway downstream of RIPK3 remains largely unknown, although ROS generation, calcium overload, and the opening of the mitochondrial permeability transition pore have been implicated (PMID:22265414)). A necroptotic signaling pathway may also be induced by alkylating DNA damage (possibly by the overactivation of poly(ADP-ribose) polymerase 1, PARP1). This is sometimes referred to as PARP-dependent cell death or parthanatos; it is still being debated if it constitutes an independent cell death modality.
synonym: "necroptosis signaling" RELATED 
synonym: "necroptosis signaling pathway" EXACT 
synonym: "necroptotic signal transduction" EXACT [GOC:signaling]
synonym: "necroptotic signalling pathway" RELATED 
is_a: GO:0007165 ! signal transduction
relationship: part_of: GO:0070266 ! necroptotic process
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