Editing Apoptosis (section)

===Extrinsic pathway===
[[File:signal transduction pathways.png|thumb|500px|right|Overview of signal transduction pathways]]
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| footer            = Overview of TNF (left) and Fas (right) signalling in apoptosis, an example of direct signal transduction
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Two theories of the direct initiation of apoptotic mechanisms in mammals have been suggested: the ''TNF-induced'' ([[tumor necrosis factor]]) model and the  ''Fas-Fas [[ligand]]-mediated'' model, both involving receptors of the ''TNF receptor'' (TNFR) family<ref name="fas">{{cite journal | vauthors = Wajant H | title = The Fas signaling pathway: more than a paradigm | journal = Science | volume = 296 | issue = 5573 | pages = 1635–1636 | date = May 2002 | pmid = 12040174 | doi = 10.1126/science.1071553 | s2cid = 29449108 | bibcode = 2002Sci...296.1635W }}</ref> coupled to extrinsic signals.

==== TNF pathway ====
[[TNF-alpha]] is a [[cytokine]] produced mainly by activated [[macrophage]]s, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF-alpha: [[TNFR1]] and [[TNFR2]]. The binding of TNF-alpha to TNFR1 has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain ([[TRADD]]) and Fas-associated death domain protein ([[FADD]]). [[cIAP1]]/2 can inhibit TNF-α signaling by binding to [[TRAF2]]. [[CFLAR|FLIP]] inhibits the activation of caspase-8.<ref name="tnfr1">{{cite journal | vauthors = Chen G, Goeddel DV | title = TNF-R1 signaling: a beautiful pathway | journal = Science | volume = 296 | issue = 5573 | pages = 1634–1635 | date = May 2002 | pmid = 12040173 | doi = 10.1126/science.1071924 | s2cid = 25321662 | bibcode = 2002Sci...296.1634C }}</ref> Binding of this receptor can also indirectly lead to the activation of [[transcription factor]]s involved in cell survival and inflammatory responses.<ref name="tfnpathway">{{cite journal| vauthors=Goeddel, DV| title=Connection Map for Tumor Necrosis Factor Pathway| journal=[[Science Signaling|Science's STKE]]| url=http://stke.sciencemag.org/cgi/cm/CMP_7107| doi=10.1126/stke.3822007tw132| volume=2007| issue=382| pages=tw132| year=2007| s2cid=85404086| access-date=2004-01-01| archive-date=2009-07-10| archive-url=https://web.archive.org/web/20090710024231/http://stke.sciencemag.org/cgi/cm/CMP_7107| url-status=dead| url-access=subscription}}</ref> However, signalling through TNFR1 might also induce apoptosis in a caspase-independent manner.<ref name="LAPFapoptosis">{{cite journal | vauthors = Chen W, Li N, Chen T, Han Y, Li C, Wang Y, He W, Zhang L, Wan T, Cao X | display-authors = 6 | title = The lysosome-associated apoptosis-inducing protein containing the pleckstrin homology (PH) and FYVE domains (LAPF), representative of a novel family of PH and FYVE domain-containing proteins, induces caspase-independent apoptosis via the lysosomal-mitochondrial pathway | journal = The Journal of Biological Chemistry | volume = 280 | issue = 49 | pages = 40985–40995 | date = December 2005 | pmid = 16188880 | doi = 10.1074/jbc.M502190200 | doi-access = free }}{{Retracted|doi=10.1016/j.jbc.2021.100764|http://retractionwatch.com/?s=%22Xuetao+Cao%22 ''Retraction Watch''|intentional=yes}}</ref>{{better source needed|date=October 2024}} The link between TNF-alpha and apoptosis shows why an abnormal production of TNF-alpha plays a fundamental role in several human diseases, especially in [[autoimmune disease]]s. The [[TNF receptor superfamily|TNF-alpha receptor superfamily]] also includes death receptors (DRs), such as [[Death receptor 4|DR4]] and [[Death receptor 5|DR5]]. These receptors bind to the protein [[TRAIL]] and mediate apoptosis. Apoptosis is known to be one of the primary mechanisms of targeted cancer therapy.<ref>{{cite journal | vauthors = Gerl R, Vaux DL | title = Apoptosis in the development and treatment of cancer | journal = Carcinogenesis | volume = 26 | issue = 2 | pages = 263–270 | date = February 2005 | pmid = 15375012 | doi = 10.1093/carcin/bgh283 | doi-access = free }}</ref> Luminescent iridium complex-peptide hybrids (IPHs) have recently been designed, which mimic TRAIL and bind to death receptors on cancer cells, thereby inducing their apoptosis.<ref>{{cite journal | vauthors = Masum AA, Yokoi K, Hisamatsu Y, Naito K, Shashni B, Aoki S | title = Design and synthesis of a luminescent iridium complex-peptide hybrid (IPH) that detects cancer cells and induces their apoptosis | journal = Bioorganic & Medicinal Chemistry | volume = 26 | issue = 17 | pages = 4804–4816 | date = September 2018 | pmid = 30177492 | doi = 10.1016/j.bmc.2018.08.016 | s2cid = 52149418 }}</ref>

==== Fas pathway ====
{{main|Activation-induced cell death}}

The [[fas receptor]]  (First apoptosis signal) – (also known as ''Apo-1'' or ''CD95'') is a [[transmembrane protein]] of the TNF family which binds the [[FAS ligand|Fas ligand]] (FasL).<ref name="fas"/> The interaction between Fas and FasL results in the formation of the ''death-inducing signaling complex'' (DISC), which contains the FADD, caspase-8 and caspase-10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase family, and triggers the execution of apoptosis of the cell. In other types of cells (type II), the ''Fas''-DISC starts a feedback loop that spirals into increasing release of proapoptotic factors from mitochondria and the amplified activation of caspase-8.<ref name="fassignal">{{cite journal| vauthors=Wajant H| title=Connection Map for Fas Signaling Pathway| journal=[[Science Signaling|Science's STKE]]| url=http://stke.sciencemag.org/cgi/cm/CMP_7966| doi=10.1126/stke.3802007tr1| volume=2007| issue=380| pages=tr1| year=2007| s2cid=84909531| access-date=2004-01-01| archive-date=2009-05-03| archive-url=https://web.archive.org/web/20090503010824/http://stke.sciencemag.org/cgi/cm/CMP_7966| url-status=dead| url-access=subscription}}</ref>

==== Common components ====

Following ''TNF-R1'' and ''Fas'' activation in mammalian cells{{Citation needed|reason=This is only relevant Type II (pancreatic B-cells and hemaetapoetic stem cells), FAS depdnent apoptosis is indepdnent of MOMP|date=October 2020}} a balance between proapoptotic ([[Bcl-2-associated X protein|BAX]],<ref name="bax">{{cite journal | vauthors = Murphy KM, Ranganathan V, Farnsworth ML, Kavallaris M, Lock RB | title = Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells | journal = Cell Death and Differentiation | volume = 7 | issue = 1 | pages = 102–111 | date = January 2000 | pmid = 10713725 | doi = 10.1038/sj.cdd.4400597 | doi-access = free | author-link4 = Maria Kavallaris }}</ref> [[BH3 interacting domain death agonist|BID]], [[Bcl-2 homologous antagonist killer|BAK]], or [[Bcl-2-associated death promoter|BAD]]) and anti-apoptotic (''[[Bcl-Xl]]'' and ''[[Bcl-2]]'') members of the ''Bcl-2'' family are established. This balance is the proportion of proapoptotic [[Protein dimer|homodimers]] that form in the outer-membrane of the mitochondrion. The proapoptotic homodimers are required to make the mitochondrial membrane permeable for the release of caspase activators such as cytochrome c and SMAC. Control of proapoptotic proteins under normal cell conditions of nonapoptotic cells is incompletely understood, but in general, Bax or Bak are activated by the activation of BH3-only proteins, part of the [[Bcl-2]] family.<ref>{{cite journal | vauthors = Westphal D, Kluck RM, Dewson G | title = Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis | journal = Cell Death and Differentiation | volume = 21 | issue = 2 | pages = 196–205 | date = February 2014 | pmid = 24162660 | pmc = 3890949 | doi = 10.1038/cdd.2013.139 }}</ref>

==== Caspases ====
[[Caspase]]s  play the central role in the transduction of ER apoptotic signals. Caspases are proteins that are highly conserved, cysteine-dependent aspartate-specific proteases. There are two types of caspases: initiator caspases (caspases 2, 8, 9, 10, 11, and 12) and effector caspases (caspases 3, 6, and 7). The activation of initiator caspases requires binding to specific oligomeric [[APAF1|activator protein]]. Effector caspases are then activated by these active initiator caspases through [[Proteolysis|proteolytic]] cleavage. The active effector caspases then proteolytically degrade a host of intracellular proteins to carry out the cell death program.{{citation needed|date=November 2024}}

==== Caspase-independent apoptotic pathway ====
There also exists a caspase-independent apoptotic pathway that is mediated by AIF ([[apoptosis-inducing factor]]).<ref name="pmid9989411">{{cite journal | vauthors = Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G | display-authors = 6 | title = Molecular characterization of mitochondrial apoptosis-inducing factor | journal = Nature | volume = 397 | issue = 6718 | pages = 441–446 | date = February 1999 | pmid = 9989411 | doi = 10.1038/17135 | s2cid = 204991081 | bibcode = 1999Natur.397..441S }}</ref>