Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005031 tumor necrosis factor receptor activity	IBA GO_REF:0000033	ACCEPT	Summary: CORE FUNCTION of FAS. FAS/CD95 is a type I transmembrane death receptor that binds FASLG (FasL/CD95L) and mediates apoptotic signaling. FAS is a bona fide member of the TNF receptor superfamily (TNFRSF6), containing three cysteine-rich domains (CRDs) in its extracellular region characteristic of this family [PMID:1375228]. Note: This annotation applies primarily to membrane-bound isoform 1 (P25445-1); soluble isoforms retain ligand binding but lack signaling capacity. Reason: This is a core molecular function of FAS. The deep research confirms FAS is TNFRSF6 with characteristic cysteine-rich domains that mediate FasL binding. IBA inference is appropriate as this function is highly conserved across the TNFR family. Supporting Evidence: PMID:1375228 The deduced amino acid sequence of APO-1 showed sequence identity with the Fas antigen, a cysteine-rich transmembrane protein of 335 amino acids with significant similarity to the members of the tumor necrosis factor/nerve growth factor receptor superfamily. file:human/FAS/FAS-deep-research-perplexity.md provider: perplexity
GO:0045121 membrane raft	IBA GO_REF:0000033	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS localizes to cholesterol- and sphingolipid-rich membrane rafts, which is important for efficient DISC assembly and apoptotic signaling. Caveolin-1 regulates Fas localization and DISC formation in membrane rafts [PMID:21382479]. The deep research confirms membrane raft localization facilitates FAS clustering upon FasL binding. Reason: Well-supported localization for membrane-bound FAS isoform 1. IBA inference is consistent with direct experimental evidence (IDA PMID:21382479). Note: Does not apply to soluble isoforms 2-6 which are secreted. Supporting Evidence: PMID:21382479 We found that Cav-1 regulated Fas signaling and mediated the communication between extrinsic and intrinsic pathways. Shortly after hyperoxia (4 h), the colocalization and interaction of Cav-1 and Fas increased, followed by Fas multimer and DISC formation.
GO:0009897 external side of plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). The extracellular domain of membrane-bound FAS is exposed on the external side of the plasma membrane where it binds FasL. FAS is a type I transmembrane protein with the N-terminal CRD-containing ligand-binding domain facing the extracellular space [PMID:1375228]. Reason: Correct localization for the canonical membrane-bound isoform 1. This is essential for FasL binding and receptor function. Note: Soluble isoforms 2-6 are secreted and do not have this localization. Supporting Evidence: PMID:1375228 The APO-1 antigen as defined by the mouse monoclonal antibody anti-APO-1 was previously found to be expressed on the cell surface of activated human T and B lymphocytes and a variety of malignant human lymphoid cell lines.
GO:0006924 activation-induced cell death of T cells	IBA GO_REF:0000033	ACCEPT	Summary: CORE FUNCTION of membrane-bound FAS. Activation-induced cell death (AICD) is a critical mechanism for T cell homeostasis where repeated TCR stimulation induces FAS and FasL expression, creating an autocrine/paracrine death signal that terminates immune responses. The deep research (FAS-deep-research-perplexity.md) confirms FAS-FasL interactions participate in AICD of mature T-cells. Reason: Well-established core function of FAS in immune regulation. AICD via FAS-FasL is essential for peripheral tolerance and termination of immune responses. Defects in this pathway cause ALPS (autoimmune lymphoproliferative syndrome). Supporting Evidence: PMID:7538907 Overexpression of FADD in MCF7 and BJAB cells induces apoptosis, which, like Fas-induced apoptosis, is blocked by CrmA, a specific inhibitor of the interleukin-1 beta-converting enzyme.
GO:0031265 CD95 death-inducing signaling complex	IBA GO_REF:0000033	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS is a core component of the CD95 death-inducing signaling complex (DISC), which forms upon FasL binding and consists of FAS, FADD, and procaspase-8. The Fas-FADD death domain complex forms an asymmetric oligomeric structure of 5-7 Fas DD and 5 FADD DD [PMID:20935634]. This is the defining functional complex for FAS-mediated apoptosis. Reason: DISC localization is the core functional context for membrane-bound FAS. Structural studies confirm the oligomeric Fas-FADD complex architecture. Note: Soluble FAS isoforms cannot form DISC as they lack the transmembrane domain needed for membrane anchoring and proper DISC assembly. Supporting Evidence: PMID:20935634 The death-inducing signaling complex (DISC) formed by the death receptor Fas, the adaptor protein FADD and caspase-8 mediates the extrinsic apoptotic program
GO:0032872 regulation of stress-activated MAPK cascade	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: FAS ligation activates stress-activated protein kinases including ASK1 and JNK/SAPK under certain conditions, particularly glutamine deprivation [PMID:11096076]. This represents a non-apoptotic signaling output of FAS activation that can modulate cellular stress responses. Reason: FAS can regulate MAPK cascades but this is not its primary function. The deep research confirms non-apoptotic signaling pathways exist but the core function remains apoptosis induction. This annotation reflects ancillary signaling. Supporting Evidence: PMID:11096076 Fas ligation activated apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK; also known as stress-activated protein kinase (SAPK)) in Gln-deprived cells
GO:0043066 negative regulation of apoptotic process	IBA GO_REF:0000033	ACCEPT	Summary: ISOFORM-SPECIFIC annotation for SOLUBLE FAS isoforms (P25445-2 to P25445-6). Soluble FAS isoforms lacking the transmembrane domain act as decoy receptors that bind FasL and block apoptosis. This is the OPPOSITE function of membrane-bound isoform 1. PMID:7510905 demonstrates soluble FAS blocks Fas-mediated apoptosis. Reason: Correct annotation but ONLY for soluble isoforms 2-6. UniProt explicitly states that secreted isoforms 2 to 6 block apoptosis in vitro. This IBA annotation likely reflects phylogenetic inference that includes soluble forms. Supporting Evidence: PMID:7510905 Supernatants from cells transfected with the variant messenger RNA blocked apoptosis induced by the antibody to Fas
GO:0097049 motor neuron apoptotic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: FAS can mediate motor neuron apoptosis. The deep research mentions FAS expression in the developing nervous system and its role in neuronal cell death. However, this represents a tissue-specific manifestation of FAS apoptotic function rather than a distinct mechanism. Reason: While FAS can mediate motor neuron apoptosis, this is a context-specific application of its general apoptotic function. The core function is death receptor activity and apoptosis induction, which applies across cell types. Motor neuron apoptosis is one of many cellular contexts where FAS functions. Supporting Evidence: PMID:7538907 Overexpression of FADD in MCF7 and BJAB cells induces apoptosis, which, like Fas-induced apoptosis, is blocked by CrmA
GO:0097527 necroptotic signaling pathway	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: FAS can trigger necroptotic cell death through RIP1 (RIPK1) when caspase activity is inhibited. FAS interacts with RIP1 via death domain interactions [PMID:7538908]. RIP-mediated necrosis involves inhibition of ADP/ATP exchange [PMID:16507998]. This represents an alternative cell death pathway downstream of FAS activation. Reason: Necroptosis is a secondary pathway activated when apoptosis is blocked. The primary function of FAS is apoptosis induction; necroptosis occurs under specific conditions (caspase inhibition). This is a valid but non-core function. Supporting Evidence: PMID:7538908 Using a genetic selection based on protein-protein interaction in yeast, we have identified two gene products that associate with the intracellular domain of Fas: Fas itself, and a novel 74 kDa protein we have named RIP
GO:0033209 tumor necrosis factor-mediated signaling pathway	IEA GO_REF:0000108	ACCEPT	Summary: FAS is a member of the TNF receptor superfamily (TNFRSF6) and mediates signaling analogous to other TNFR family members. However, FAS specifically responds to FasL (FASLG/TNFSF6), not TNF itself. The term may be overly broad. Reason: While FAS does not directly respond to TNF, it is part of the broader TNF receptor superfamily and uses similar death domain-mediated signaling mechanisms. The IEA annotation based on logical inference is acceptable as a general categorization of this signaling pathway family.
GO:0004888 transmembrane signaling receptor activity	IEA GO_REF:0000002	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS isoform 1 is a type I transmembrane receptor that binds FasL extracellularly and transduces signals intracellularly via its death domain. This is a valid parent term of the more specific GO:0005031 (tumor necrosis factor receptor activity). Reason: Correct general molecular function for membrane-bound FAS. This IEA based on InterPro domain mapping is appropriate. Note: Does not apply to soluble isoforms 2-6 which lack the transmembrane domain.
GO:0005516 calmodulin binding	IEA GO_REF:0000043	ACCEPT	Summary: FAS binds calmodulin in a region overlapping its death domain (residues 230-254). This interaction has been structurally characterized by X-ray crystallography [PMID:24914971 cited in UniProt]. Calmodulin binding may modulate FAS signaling. Reason: UniProt documents interaction with CALM based on structural evidence. IEA from keyword mapping is consistent with direct experimental data. This represents a regulatory interaction that modulates FAS function.
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: ISOFORM-SPECIFIC annotation for SOLUBLE FAS isoforms (P25445-2 to P25445-6). UniProt explicitly states that isoforms 2-6 are secreted. Soluble FAS lacking the transmembrane domain is released into the extracellular space where it acts as a decoy receptor. Reason: Correct localization for soluble FAS isoforms. IEA from UniProt subcellular location mapping is appropriate for the secreted isoforms. Note: Does not apply to membrane-bound isoform 1.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS isoform 1 is a type I transmembrane protein localized to the plasma membrane where it functions as a death receptor. UniProt confirms cell membrane localization for isoform 1. Reason: Correct localization for membrane-bound FAS. IEA from UniProt subcellular location is appropriate. Note: Does not apply to soluble isoforms 2-6 which are secreted.
GO:0006915 apoptotic process	IEA GO_REF:0000120	ACCEPT	Summary: CORE FUNCTION of membrane-bound FAS. Apoptosis is the primary biological process mediated by FAS activation. Upon FasL binding, FAS recruits FADD and caspase-8 to form the DISC, initiating the caspase cascade leading to cell death. Reason: This is the core biological process for FAS. IEA from combined automated methods is consistent with extensive experimental evidence. Note: Soluble isoforms have the opposite effect, blocking apoptosis.
GO:0006955 immune response	IEA GO_REF:0000002	ACCEPT	Summary: FAS plays a critical role in immune homeostasis through elimination of autoreactive lymphocytes and termination of immune responses via AICD. Defects in FAS cause ALPS, an autoimmune disorder. The deep research confirms FAS-FasL is essential for peripheral tolerance and immune regulation. Reason: While overly broad, FAS does function in immune response contexts. The term encompasses FAS roles in lymphocyte homeostasis, peripheral tolerance, and immune response termination. IEA from InterPro mapping is acceptable.
GO:0007165 signal transduction	IEA GO_REF:0000002	ACCEPT	Summary: FAS is a signaling receptor that transduces extracellular FasL binding into intracellular signals. The signal transduction involves death domain-mediated recruitment of FADD and caspase-8, leading to DISC formation and caspase activation. Reason: Correct but very general term. FAS is indeed a signal transducing receptor. More specific terms (e.g., Fas signaling pathway, extrinsic apoptotic signaling) better capture its function.
GO:0009986 cell surface	IEA GO_REF:0000117	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS isoform 1 is expressed on the cell surface where it can engage FasL on neighboring cells. Cell surface expression is essential for FAS-mediated apoptosis. Reason: Correct localization for membrane-bound FAS. IEA from ARBA machine learning is consistent with experimental evidence. Note: Does not apply to soluble isoforms.
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS isoform 1 is an integral membrane protein. This is a very general parent term of plasma membrane. Reason: Correct but overly general term. More specific terms (plasma membrane, membrane raft) are more informative. IEA from InterPro mapping is appropriate.
GO:0031265 CD95 death-inducing signaling complex	IEA GO_REF:0000117	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). Duplicate of IBA annotation for DISC localization. FAS is a core component of the CD95 DISC along with FADD and caspase-8. Reason: Correct localization. This IEA annotation is consistent with the IBA annotation and extensive experimental evidence. Duplicates are acceptable with different evidence codes.
GO:0042981 regulation of apoptotic process	IEA GO_REF:0000117	ACCEPT	Summary: FAS regulates apoptosis - membrane-bound isoform 1 positively regulates it by triggering cell death, while soluble isoforms 2-6 negatively regulate it by blocking FasL. This general term encompasses both activities. Reason: Correct but imprecise. The more specific child terms (positive/negative regulation of apoptotic process) better capture the isoform-specific functions. IEA is acceptable as a general categorization.
GO:0045121 membrane raft	IEA GO_REF:0000044	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). Duplicate of IBA annotation. FAS localizes to membrane rafts which facilitates DISC assembly. Reason: Correct localization. Consistent with IBA annotation and experimental evidence. IEA from UniProt confirms this localization.
GO:0097191 extrinsic apoptotic signaling pathway	IEA GO_REF:0000117	ACCEPT	Summary: CORE FUNCTION of membrane-bound FAS. FAS is the defining death receptor of the extrinsic apoptotic signaling pathway. Upon FasL binding, FAS recruits FADD via death domain interactions, forming the DISC that activates caspase-8. Reason: This is the core biological process for FAS. The extrinsic pathway is initiated by death receptors like FAS, in contrast to the intrinsic (mitochondrial) pathway. IEA from ARBA is consistent with extensive experimental evidence.
GO:0005515 protein binding	IPI PMID:10918185 Negative regulation of Fas-mediated apoptosis by FAP-1 in hu...	MODIFY	Summary: Generic protein binding term. FAS interacts with many proteins including FADD, CASP8, RIPK1, DAXX, and others. This term is uninformative and should be replaced with more specific molecular function terms. Reason: Per curation guidelines, 'protein binding' is too vague and does not provide useful information about FAS function. More specific terms should be used. Proposed replacements: tumor necrosis factor receptor activity identical protein binding Supporting Evidence: PMID:10918185 Negative regulation of Fas-mediated apoptosis by FAP-1 in human cancer cells.
GO:0005515 protein binding	IPI PMID:11003656 Inhibition of Daxx-mediated apoptosis by heat shock protein ...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. More specific molecular function terms should be used. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:11003656 Inhibition of Daxx-mediated apoptosis by heat shock protein 27.
GO:0005515 protein binding	IPI PMID:11495919 Apoptosis signal-regulating kinase 1 controls the proapoptot...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:11495919 2001 Aug 8. Apoptosis signal-regulating kinase 1 controls the proapoptotic function of death-associated protein (Daxx) in the cytoplasm.
GO:0005515 protein binding	IPI PMID:11606059 Apoptosis-linked gene 2 binds to the death domain of Fas and...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:11606059 Apoptosis-linked gene 2 binds to the death domain of Fas and dissociates from Fas during Fas-mediated apoptosis in Jurkat cells.
GO:0005515 protein binding	IPI PMID:11717445 Caspase-10 is an initiator caspase in death receptor signali...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:11717445 Caspase-10 is an initiator caspase in death receptor signaling.
GO:0005515 protein binding	IPI PMID:12724420 FAP-1 association with Fas (Apo-1) inhibits Fas expression o...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:12724420 FAP-1 association with Fas (Apo-1) inhibits Fas expression on the cell surface.
GO:0005515 protein binding	IPI PMID:12887920 Induction of TNF receptor I-mediated apoptosis via two seque...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:12887920 Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.
GO:0005515 protein binding	IPI PMID:16498403 The role of receptor internalization in CD95 signaling.	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:16498403 The role of receptor internalization in CD95 signaling.
GO:0005515 protein binding	IPI PMID:17047155 Caspase-8 prevents sustained activation of NF-kappaB in mono...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:17047155 2006 Oct 17. Caspase-8 prevents sustained activation of NF-kappaB in monocytes undergoing macrophagic differentiation.
GO:0005515 protein binding	IPI PMID:17159907 Palmitoylation of CD95 facilitates formation of SDS-stable r...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:17159907 Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling.
GO:0005515 protein binding	IPI PMID:18328427 Yes and PI3K bind CD95 to signal invasion of glioblastoma.	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:18328427 Yes and PI3K bind CD95 to signal invasion of glioblastoma.
GO:0005515 protein binding	IPI PMID:21382479 Caveolin-1 mediates Fas-BID signaling in hyperoxia-induced a...	MODIFY	Summary: FAS-Caveolin-1 interaction study. Cav-1 regulates Fas signaling and DISC formation. Generic protein binding term is uninformative. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:21382479 the colocalization and interaction of Cav-1 and Fas increased, followed by Fas multimer and DISC formation
GO:0005515 protein binding	IPI PMID:21625644 Modulation of the CD95-induced apoptosis: the role of CD95 N...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:21625644 Modulation of the CD95-induced apoptosis: the role of CD95 N-glycosylation.
GO:0005515 protein binding	IPI PMID:21803845 PMLRARα binds to Fas and suppresses Fas-mediated apoptosis t...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:21803845 2011 Jul 29. PMLRARα binds to Fas and suppresses Fas-mediated apoptosis through recruiting c-FLIP in vivo.
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:25241761 Oct 9. Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:35922511 A physical wiring diagram for the human immune system.	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:35922511 Aug 3. A physical wiring diagram for the human immune system.
GO:0005515 protein binding	IPI PMID:7536190 A novel protein that interacts with the death domain of Fas/...	MODIFY	Summary: FAS-FADD interaction. This study identified FADD as binding the FAS death domain. More specific term needed. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:7536190 A novel protein that specifically binds to the death domain of Fas/APO1 but not to Fas/APO1 molecules with a loss of function point mutation
GO:0005515 protein binding	IPI PMID:7538907 FADD, a novel death domain-containing protein, interacts wit...	MODIFY	Summary: FAS-FADD interaction via death domains. More specific term needed. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:7538907 FADD, which binds Fas and Fas-FD5, a mutant of Fas possessing enhanced killing activity, but not the functionally inactive mutants Fas-LPR and Fas-FD8
GO:0042802 identical protein binding	IPI PMID:21382479 Caveolin-1 mediates Fas-BID signaling in hyperoxia-induced a...	ACCEPT	Summary: FAS self-association/multimerization. FAS forms multimers upon activation which is required for DISC assembly. This is a valid more specific term than generic protein binding. Reason: FAS self-association is well-documented and important for signaling. The Fas-FADD death domain complex contains 5-7 FAS molecules, demonstrating FAS homo-oligomerization. Supporting Evidence: PMID:21382479 the colocalization and interaction of Cav-1 and Fas increased, followed by Fas multimer and DISC formation
GO:0042802 identical protein binding	IPI PMID:7536190 A novel protein that interacts with the death domain of Fas/...	ACCEPT	Summary: FAS self-association. The death domain mediates FAS-FAS interactions. Reason: FAS self-association via death domains is well-established. Required for DISC assembly. Supporting Evidence: PMID:7536190 the region upstream to the death domain prompts self-association of the protein
GO:0042802 identical protein binding	IPI PMID:7538908 RIP: a novel protein containing a death domain that interact...	ACCEPT	Summary: FAS self-association identified in yeast two-hybrid screen. Reason: FAS-FAS interaction documented by RIP study. Consistent with DISC architecture. Supporting Evidence: PMID:7538908 we have identified two gene products that associate with the intracellular domain of Fas: Fas itself, and a novel 74 kDa protein we have named RIP
GO:0005886 plasma membrane	IDA GO_REF:0000052	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). Direct experimental evidence (HPA immunohistochemistry) for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. IDA from HPA data is strong evidence. Note: Does not apply to soluble isoforms.
GO:0005031 tumor necrosis factor receptor activity	IDA PMID:12221075 Glutathione peroxidase-1 protects from CD95-induced apoptosi...	ACCEPT	Summary: CORE FUNCTION. Direct experimental demonstration of TNF receptor activity. FAS binds FasL and activates downstream apoptotic signaling. Reason: This is the core molecular function of FAS. IDA evidence from direct assay confirms receptor activity. Consistent with IBA annotation. Supporting Evidence: PMID:12221075 Through the induction of apoptosis, CD95 plays a crucial role in the immune response and the elimination of cancer cells
GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors	IDA PMID:12221075 Glutathione peroxidase-1 protects from CD95-induced apoptosi...	ACCEPT	Summary: CORE FUNCTION of membrane-bound FAS. FAS is the canonical death domain receptor that initiates the extrinsic apoptotic pathway. This is a highly specific and accurate term for FAS function. Reason: This is the defining biological process for FAS. The term precisely describes FAS-mediated apoptosis through death domain interactions with FADD. Supporting Evidence: PMID:12221075 Ligation of CD95 receptor activates a complex signaling network that appears to implicate the generation of reactive oxygen species (ROS)
GO:0036337 Fas signaling pathway	IDA PMID:12221075 Glutathione peroxidase-1 protects from CD95-induced apoptosi...	ACCEPT	Summary: CORE FUNCTION. The Fas signaling pathway is the specific pathway initiated by FAS/CD95 ligation. This is the most precise process term for FAS function. Reason: This is the defining signaling pathway for FAS. Highly specific and accurate. Supporting Evidence: PMID:12221075 Ligation of CD95 receptor activates a complex signaling network
GO:1903428 positive regulation of reactive oxygen species biosynthetic process	IDA PMID:12221075 Glutathione peroxidase-1 protects from CD95-induced apoptosi...	KEEP AS NON CORE	Summary: FAS activation triggers early ROS production. This study demonstrated that anti-CD95 antibodies triggered early generation of ROS in T47D cells. Reason: ROS production is a documented downstream effect of FAS signaling but is not the core function. The primary function is apoptosis induction. Supporting Evidence: PMID:12221075 Anti-CD95 antibodies triggered an early generation of ROS in human breast cancer T47D cells
GO:0005515 protein binding	IPI PMID:15917238 CD47 augments Fas/CD95-mediated apoptosis.	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:15917238 2005 May 24. CD47 augments Fas/CD95-mediated apoptosis.
GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors	IDA PMID:9333124 Fas and Fas ligand interaction is necessary for human osteob...	ACCEPT	Summary: CORE FUNCTION. Duplicate annotation for extrinsic apoptotic signaling via death domain receptors from different publication. Reason: Core biological process for FAS. Consistent with other annotations. Supporting Evidence: PMID:9333124 Fas and Fas ligand interaction is necessary for human osteoblast apoptosis.
GO:0005515 protein binding	IPI PMID:18846110 Identification of an antiapoptotic protein complex at death ...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:18846110 2008 Oct 10. Identification of an antiapoptotic protein complex at death receptors.
GO:0032872 regulation of stress-activated MAPK cascade	IMP PMID:11096076 Glutamine-dependent antiapoptotic interaction of human gluta...	KEEP AS NON CORE	Summary: FAS ligation activates ASK1 and JNK/SAPK under glutamine deprivation conditions. Duplicate of IBA annotation with experimental evidence. Reason: MAPK regulation is a secondary signaling output, not the core function of FAS. Supporting Evidence: PMID:11096076 Fas ligation activated apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK; also known as stress-activated protein kinase (SAPK)) in Gln-deprived cells
GO:0034198 cellular response to amino acid starvation	IMP PMID:11096076 Glutamine-dependent antiapoptotic interaction of human gluta...	KEEP AS NON CORE	Summary: FAS-mediated apoptosis is enhanced under glutamine starvation conditions. This reflects context-dependent modulation of FAS signaling. Reason: Amino acid starvation modulates FAS sensitivity but is not a core function. Supporting Evidence: PMID:11096076 HeLa cells were susceptible to Fas-mediated apoptosis under the condition of glutamine deprivation
GO:0036337 Fas signaling pathway	IMP PMID:11096076 Glutamine-dependent antiapoptotic interaction of human gluta...	ACCEPT	Summary: CORE FUNCTION. Duplicate annotation for Fas signaling pathway with IMP evidence. Reason: Core signaling pathway for FAS. Consistent with IDA annotation. Supporting Evidence: PMID:11096076 HeLa cells were susceptible to Fas-mediated apoptosis
GO:2001235 positive regulation of apoptotic signaling pathway	IMP PMID:11096076 Glutamine-dependent antiapoptotic interaction of human gluta...	ACCEPT	Summary: CORE FUNCTION of membrane-bound FAS. FAS positively regulates apoptotic signaling by initiating the caspase cascade. Reason: Core function of membrane-bound FAS isoform 1. Note: Soluble isoforms have opposite effect. Supporting Evidence: PMID:11096076 HeLa cells were susceptible to Fas-mediated apoptosis
GO:0005516 calmodulin binding	IDA PMID:24914971 Structural insights into the mechanism of calmodulin binding...	ACCEPT	Summary: FAS binds calmodulin in a region overlapping its death domain (residues 230-254). Direct experimental evidence from structural studies. Reason: IDA evidence supports calmodulin binding. This may modulate FAS signaling. Consistent with IEA annotation. Supporting Evidence: PMID:24914971 Structural insights into the mechanism of calmodulin binding to death receptors.
GO:0031264 death-inducing signaling complex	IDA PMID:21803845 PMLRARα binds to Fas and suppresses Fas-mediated apoptosis t...	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS is a core component of the DISC. This is a more general term than GO:0031265 (CD95 DISC). Reason: Correct localization. DISC is the functional context for FAS-mediated apoptosis. Supporting Evidence: PMID:21803845 2011 Jul 29. PMLRARα binds to Fas and suppresses Fas-mediated apoptosis through recruiting c-FLIP in vivo.
GO:0097527 necroptotic signaling pathway	IMP PMID:16507998 Inhibition of ADP/ATP exchange in receptor-interacting prote...	KEEP AS NON CORE	Summary: FAS can trigger necroptosis via RIP1 when caspases are inhibited. IMP evidence from study showing RIP-dependent necrosis downstream of death receptor ligation. Reason: Necroptosis is a secondary pathway activated when apoptosis is blocked. Consistent with IBA annotation. Supporting Evidence: PMID:16507998 These observations demonstrate a novel mechanism initiated through death receptor ligation and mediated by RIP that results in the suppression of ANT activity and necrosis
GO:0005886 plasma membrane	IMP PMID:21625644 Modulation of the CD95-induced apoptosis: the role of CD95 N...	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). IMP evidence for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Consistent with IDA and IEA annotations. Supporting Evidence: PMID:21625644 Modulation of the CD95-induced apoptosis: the role of CD95 N-glycosylation.
GO:0043065 positive regulation of apoptotic process	IDA PMID:21625644 Modulation of the CD95-induced apoptosis: the role of CD95 N...	ACCEPT	Summary: CORE FUNCTION of membrane-bound FAS (isoform 1, P25445-1). FAS is the death receptor that initiates extrinsic apoptosis by forming the DISC (Death-Inducing Signaling Complex) with FADD and CASP8 upon FasL binding. Note: This function is OPPOSITE to soluble FAS isoforms (P25445-2 to P25445-6) which BLOCK apoptosis. Reason: Core pro-apoptotic function of canonical membrane-bound FAS. Should ideally be isoform-specific to P25445-1 to distinguish from the anti-apoptotic soluble isoforms. Supporting Evidence: PMID:21625644 Modulation of the CD95-induced apoptosis: the role of CD95 N-glycosylation.
GO:0009986 cell surface	IDA PMID:22891283 Vesicles released by activated T cells induce both Fas-media...	ACCEPT	Summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). Direct experimental evidence for cell surface localization. Reason: Correct localization for membrane-bound FAS. Consistent with other annotations. Supporting Evidence: PMID:22891283 2012 Aug 13. Vesicles released by activated T cells induce both Fas-mediated RIP-dependent apoptotic and Fas-independent nonapoptotic cell deaths.
GO:0097191 extrinsic apoptotic signaling pathway	IMP PMID:22891283 Vesicles released by activated T cells induce both Fas-media...	ACCEPT	Summary: CORE FUNCTION. IMP evidence for extrinsic apoptotic signaling pathway. Consistent with IEA annotation. Reason: Core biological process for FAS. Supporting Evidence: PMID:22891283 2012 Aug 13. Vesicles released by activated T cells induce both Fas-mediated RIP-dependent apoptotic and Fas-independent nonapoptotic cell deaths.
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	KEEP AS NON CORE	Summary: FAS has been detected in extracellular exosomes. High-throughput data analysis. Reason: Exosomal localization may reflect secretion of soluble FAS isoforms or membrane FAS in exosomes. Not a core localization. Supporting Evidence: PMID:20458337 2010 May 11. MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-139952	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Consistent with other annotations.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-141310	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Duplicate from different pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3465429	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Duplicate from different pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3465448	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Duplicate from different pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3465459	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Duplicate from different pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5675456	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Duplicate from different pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6800001	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Duplicate from different pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-71050	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Duplicate from different pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-73945	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Duplicate from different pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-75244	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Duplicate from different pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-83586	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Duplicate from different pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-83650	ACCEPT	Summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane localization. Reason: Correct localization for membrane-bound FAS. Duplicate from different pathway.
GO:0071455 cellular response to hyperoxia	IMP PMID:21382479 Caveolin-1 mediates Fas-BID signaling in hyperoxia-induced a...	KEEP AS NON CORE	Summary: FAS-mediated apoptosis is induced by hyperoxia. Study showed Cav-1 regulates Fas signaling in hyperoxia-induced apoptosis. Reason: Hyperoxia response is a specific context where FAS is activated. Not a core function. Supporting Evidence: PMID:21382479 We found that Cav-1 regulated Fas signaling and mediated the communication between extrinsic and intrinsic pathways
GO:0031265 CD95 death-inducing signaling complex	IDA PMID:20935634 The Fas-FADD death domain complex structure reveals the basi...	ACCEPT	Summary: ISOFORM-SPECIFIC. Direct structural evidence for FAS in the CD95 DISC. This study solved the Fas-FADD death domain complex structure showing 5-7 Fas DD and 5 FADD DD. Reason: Core localization for membrane-bound FAS. Strong structural evidence. Supporting Evidence: PMID:20935634 The death-inducing signaling complex (DISC) formed by the death receptor Fas, the adaptor protein FADD and caspase-8 mediates the extrinsic apoptotic program
GO:0043065 positive regulation of apoptotic process	IMP PMID:20935634 The Fas-FADD death domain complex structure reveals the basi...	ACCEPT	Summary: CORE FUNCTION of membrane-bound FAS. IMP evidence from structure-function studies showing that ALPS mutations disrupt FAS-FADD interaction and apoptosis. Reason: Core pro-apoptotic function. Consistent with other annotations. Supporting Evidence: PMID:20935634 Mutations in Fas that disrupt the DISC cause autoimmune lymphoproliferative syndrome (ALPS)
GO:0045121 membrane raft	IDA PMID:21382479 Caveolin-1 mediates Fas-BID signaling in hyperoxia-induced a...	ACCEPT	Summary: ISOFORM-SPECIFIC. Direct experimental evidence for FAS localization in membrane rafts. Cav-1 interaction facilitates FAS clustering in rafts. Reason: Correct localization for membrane-bound FAS. IDA evidence is strong. Supporting Evidence: PMID:21382479 the colocalization and interaction of Cav-1 and Fas increased, followed by Fas multimer and DISC formation
GO:0005515 protein binding	IPI PMID:21109225 Whole-exome-sequencing-based discovery of human FADD deficie...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:21109225 Epub 2010 Nov 25. Whole-exome-sequencing-based discovery of human FADD deficiency.
GO:0071260 cellular response to mechanical stimulus	IEP PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer...	KEEP AS NON CORE	Summary: FAS expression is modulated by mechanical stimulus. IEP (expression pattern) evidence suggests FAS is involved in cellular response to mechanical stress. Reason: Mechanical stimulus response is a specific context. IEP evidence is weaker than direct functional evidence. Supporting Evidence: PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer growth.
GO:0031264 death-inducing signaling complex	IDA PMID:11101870 Fas triggers an alternative, caspase-8-independent cell deat...	ACCEPT	Summary: ISOFORM-SPECIFIC. Direct experimental evidence for FAS in the DISC. Consistent with other DISC annotations. Reason: Core localization for membrane-bound FAS. Supporting Evidence: PMID:11101870 Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule.
GO:0019900 kinase binding	IPI PMID:7538908 RIP: a novel protein containing a death domain that interact...	ACCEPT	Summary: FAS binds RIP1 (RIPK1), a serine/threonine kinase. RIP contains a kinase domain and interacts with FAS death domain. Reason: Valid molecular function annotation. RIP1 kinase binding is well-documented. Supporting Evidence: PMID:7538908 RIP contains an N-terminal region with homology to protein kinases and a C-terminal region containing a cytoplasmic motif (death domain)
GO:0006915 apoptotic process	IDA PMID:9681877 Effect of age and apoptosis on the mouse homologue of the hu...	ACCEPT	Summary: CORE FUNCTION. Direct experimental evidence for FAS-mediated apoptosis. Reason: Core biological process for membrane-bound FAS. Consistent with other annotations. Supporting Evidence: PMID:9681877 Effect of age and apoptosis on the mouse homologue of the huWRN gene.
GO:0005515 protein binding	IPI PMID:15465831 A death receptor-associated anti-apoptotic protein, BRE, inh...	MODIFY	Summary: Generic protein binding term. Uninformative about FAS function. Reason: Per curation guidelines, 'protein binding' is too vague. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:15465831 2004 Oct 1. A death receptor-associated anti-apoptotic protein, BRE, inhibits mitochondrial apoptotic pathway.
GO:0042981 regulation of apoptotic process	NAS PMID:7533181 Three functional soluble forms of the human apoptosis-induci...	ACCEPT	Summary: FAS regulates apoptosis - membrane-bound form triggers it, soluble forms block it. NAS evidence from review article. Reason: Correct general term. Consistent with IEA annotation. Supporting Evidence: PMID:7533181 Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing.
GO:0006915 apoptotic process	TAS PMID:10871852 p38 protects human melanoma cells from UV-induced apoptosis ...	ACCEPT	Summary: CORE FUNCTION. TAS evidence for apoptotic process involvement. Reason: Core biological process for FAS. Consistent with other annotations. Supporting Evidence: PMID:10871852 p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF-kappaB activity and Fas expression.
GO:0006915 apoptotic process	TAS PMID:1375228 Purification and molecular cloning of the APO-1 cell surface...	ACCEPT	Summary: CORE FUNCTION. Original characterization of APO-1/Fas showing apoptosis induction. Reason: Core biological process. Seminal paper identifying APO-1/Fas as apoptosis inducer. Supporting Evidence: PMID:1375228 Cross-linking of the APO-1 antigen by anti-APO-1 induced programmed cell death, apoptosis, of APO-1 positive cells
GO:0007165 signal transduction	TAS PMID:9360929 Requirement for the CD95 receptor-ligand pathway in c-Myc-in...	ACCEPT	Summary: FAS is a signaling receptor. TAS evidence for signal transduction. Reason: Correct but general term. Consistent with IEA annotation. Supporting Evidence: PMID:9360929 Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis.
GO:0038023 signaling receptor activity	TAS PMID:1375228 Purification and molecular cloning of the APO-1 cell surface...	ACCEPT	Summary: CORE FUNCTION. FAS is a cell surface signaling receptor. Reason: Correct molecular function. Consistent with other annotations. Supporting Evidence: PMID:1375228 The APO-1 antigen as defined by the mouse monoclonal antibody anti-APO-1 was previously found to be expressed on the cell surface
GO:0043066 negative regulation of apoptotic process	TAS PMID:7510905 Protection from Fas-mediated apoptosis by a soluble form of ...	ACCEPT	Summary: ISOFORM-SPECIFIC ANNOTATION. This annotation refers to SOLUBLE FAS isoforms (P25445-2 to P25445-6), NOT the canonical membrane-bound form. PMID:7510905 explicitly demonstrates that "a human Fas messenger RNA variant capable of encoding a soluble Fas molecule lacking the transmembrane domain" produces a protein where "Supernatants from cells transfected with the variant messenger RNA blocked apoptosis induced by the antibody to Fas." Reason: Correct annotation for soluble FAS isoforms. This is the antagonistic function of the TMdel isoforms that act as decoy receptors. Should ideally be annotated to specific isoforms P25445-2/6, not the canonical membrane-bound P25445-1. Supporting Evidence: PMID:7510905 Supernatants from cells transfected with the variant messenger RNA blocked apoptosis induced by the antibody to Fas
GO:0065003 protein-containing complex assembly	TAS PMID:10875918 Fas preassociation required for apoptosis signaling and domi...	ACCEPT	Summary: FAS forms preassociated complexes before ligand binding. This study showed that FAS preassociation in the PRELIGAND assembly domain is required for signaling. Reason: Valid biological process. FAS preassociation and DISC assembly are well-documented. Supporting Evidence: PMID:10875918 Preassociated Fas complexes were found in living cells by means of fluorescence resonance energy transfer between variants of green fluorescent protein
GO:0005829 cytosol	NAS PMID:7533181 Three functional soluble forms of the human apoptosis-induci...	UNDECIDED	Summary: Cytosolic localization may refer to the intracellular death domain portion of membrane-bound FAS or to cleaved/soluble forms. NAS evidence is weak. Reason: Unclear what cytosolic localization refers to. FAS is primarily a membrane protein. May refer to cleaved forms or ICD. NAS evidence insufficient for confident assessment. Supporting Evidence: PMID:7533181 Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing.
GO:0038023 signaling receptor activity	NAS PMID:7533181 Three functional soluble forms of the human apoptosis-induci...	ACCEPT	Summary: CORE FUNCTION. FAS is a signaling receptor. NAS evidence from review article. Reason: Correct molecular function. Consistent with TAS annotation. Supporting Evidence: PMID:7533181 Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing.

Core Functions

FAS (CD95/APO-1) is a type I transmembrane death receptor of the TNF receptor superfamily (TNFRSF6). The extracellular domain contains three cysteine-rich domains (CRDs) that bind FasL (FASLG/CD95L). This is the defining molecular function of FAS. ISOFORM-SPECIFIC to membrane-bound isoform 1 (P25445-1).

Molecular Function:

tumor necrosis factor receptor activity

Directly Involved In:

extrinsic apoptotic signaling pathway via death domain receptors Fas signaling pathway

Cellular Locations:

external side of plasma membrane membrane raft

In Complex:

CD95 death-inducing signaling complex

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10871852

p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF-kappaB activity and Fas expression.

PMID:10875918

Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations.

PMID:10918185

Negative regulation of Fas-mediated apoptosis by FAP-1 in human cancer cells.

PMID:11003656

Inhibition of Daxx-mediated apoptosis by heat shock protein 27.

PMID:11096076

Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1.

PMID:11101870

Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule.

PMID:11495919

Apoptosis signal-regulating kinase 1 controls the proapoptotic function of death-associated protein (Daxx) in the cytoplasm.

PMID:11606059

Apoptosis-linked gene 2 binds to the death domain of Fas and dissociates from Fas during Fas-mediated apoptosis in Jurkat cells.

PMID:11717445

Caspase-10 is an initiator caspase in death receptor signaling.

PMID:12221075

Glutathione peroxidase-1 protects from CD95-induced apoptosis.

PMID:12724420

FAP-1 association with Fas (Apo-1) inhibits Fas expression on the cell surface.

PMID:12887920

Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

PMID:1375228

Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen.

PMID:15465831

A death receptor-associated anti-apoptotic protein, BRE, inhibits mitochondrial apoptotic pathway.

PMID:15917238

CD47 augments Fas/CD95-mediated apoptosis.

PMID:16498403

The role of receptor internalization in CD95 signaling.

PMID:16507998

Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis.

PMID:17047155

Caspase-8 prevents sustained activation of NF-kappaB in monocytes undergoing macrophagic differentiation.

PMID:17159907

Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling.

PMID:18328427

Yes and PI3K bind CD95 to signal invasion of glioblastoma.

PMID:18846110

Identification of an antiapoptotic protein complex at death receptors.

PMID:19593445

Expression of the Bcl-2 protein BAD promotes prostate cancer growth.

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

PMID:20935634

The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations.

PMID:21109225

Whole-exome-sequencing-based discovery of human FADD deficiency.

PMID:21382479

Caveolin-1 mediates Fas-BID signaling in hyperoxia-induced apoptosis.

PMID:21625644

Modulation of the CD95-induced apoptosis: the role of CD95 N-glycosylation.

PMID:21803845

PMLRARα binds to Fas and suppresses Fas-mediated apoptosis through recruiting c-FLIP in vivo.

PMID:22891283

Vesicles released by activated T cells induce both Fas-mediated RIP-dependent apoptotic and Fas-independent nonapoptotic cell deaths.

PMID:24914971

Structural insights into the mechanism of calmodulin binding to death receptors.

PMID:25241761

Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35922511

A physical wiring diagram for the human immune system.

PMID:7510905

Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule.

PMID:7533181

Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing.

PMID:7536190

A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain.

PMID:7538907

FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.

PMID:7538908

RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death.

PMID:9333124

Fas and Fas ligand interaction is necessary for human osteoblast apoptosis.

PMID:9360929

Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis.

PMID:9681877

Effect of age and apoptosis on the mouse homologue of the huWRN gene.

Reactome:R-HSA-139952

Caspase-8 processing in the DISC

Reactome:R-HSA-141310

FASL:FAS Receptor Trimer:FADD complex binds procaspase-10

Reactome:R-HSA-3465429

FLIP(S) and procaspase-8 form heterodimer

Reactome:R-HSA-3465448

Caspase-8 and FLIP(L) processing at DISC

Reactome:R-HSA-3465459

FLIP(L) and procaspase-8 form heterodimer in FasL/CD95 signaling

Reactome:R-HSA-5675456

FLIP(L) and procaspase-8 form heterodimer

Reactome:R-HSA-6800001

TP53 family members stimulate FAS gene expression

Reactome:R-HSA-71050

Trimerization of the FASL:FAS receptor complex

Reactome:R-HSA-73945

FAS-mediated dimerization of procaspase-8

Reactome:R-HSA-75244

FASL binds FAS Receptor

Reactome:R-HSA-83586

FASL:FAS Receptor Trimer:FADD complex binds pro-Caspase-8

Reactome:R-HSA-83650

FasL:Fas binds FADD

file:human/FAS/FAS-deep-research-perplexity.md

Deep research report on FAS

📚 Additional Documentation

Deep Research Perplexity

(FAS-deep-research-perplexity.md)

provider: perplexity
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template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: FAS
gene_symbol: FAS
uniprot_accession: P25445
protein_description: 'RecName: Full=Tumor necrosis factor receptor superfamily member
6; AltName: Full=Apo-1 antigen; AltName: Full=Apoptosis-mediating surface antigen
FAS; AltName: Full=FASLG receptor; AltName: CD_antigen=CD95; Flags: Precursor;'
gene_info: Name=FAS; Synonyms=APT1, FAS1, TNFRSF6;
organism_full: Homo sapiens (Human).
protein_family: Not specified in UniProt
protein_domains: DEATH-like_dom_sf. (IPR011029); Death_dom. (IPR000488); Fas_rcpt.
(IPR008063); TNFR/NGFR_Cys_rich_reg. (IPR001368); TNFRSF6_death. (IPR033998)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P25445
Protein Description: RecName: Full=Tumor necrosis factor receptor superfamily member 6; AltName: Full=Apo-1 antigen; AltName: Full=Apoptosis-mediating surface antigen FAS; AltName: Full=FASLG receptor; AltName: CD_antigen=CD95; Flags: Precursor;
Gene Information: Name=FAS; Synonyms=APT1, FAS1, TNFRSF6;
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: DEATH-like_dom_sf. (IPR011029); Death_dom. (IPR000488); Fas_rcpt. (IPR008063); TNFR/NGFR_Cys_rich_reg. (IPR001368); TNFRSF6_death. (IPR033998)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "FAS" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'FAS' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene FAS (gene ID: FAS, UniProt: P25445) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

The Fas Receptor (CD95/TNFRSF6): Molecular Architecture, Death-Inducing Signaling, and the Emerging Complexity of Non-Apoptotic Functions in Human Cellular Regulation

Executive Summary

The Fas receptor, encoded by the FAS gene located at chromosome 10q24.1 in humans and officially designated as tumor necrosis factor receptor superfamily member 6 (TNFRSF6), represents one of the most extensively characterized death receptors in cellular biology[1][3]. This 319-amino acid transmembrane glycoprotein, also known by its alternative designations CD95, APO-1, and APT1, functions as a primary mediator of programmed cell death through its interaction with Fas ligand (FasL/CD95L), initiating apoptosis through assembly of the death-inducing signaling complex (DISC)[1][2]. Beyond its canonical role in eliminating unwanted or autoreactive lymphocytes, emerging evidence from recent structural studies and clinical observations reveals that Fas possesses significant non-apoptotic functions mediated through alternative signaling pathways that regulate immune cell survival, migration, inflammatory responses, and metabolic processes[20][37][40]. The Fas/FasL system represents a critical regulatory node in immune homeostasis, with mutations in the FAS gene causing autoimmune lymphoproliferative syndrome (ALPS), while evolutionary changes in human FasL have paradoxically weakened immune surveillance against certain solid tumors through increased susceptibility to plasmin-mediated proteolytic inactivation[44]. This comprehensive analysis examines the molecular mechanisms of Fas-mediated apoptosis, the structural basis of DISC assembly, the tissue-specific differences in signaling pathway utilization, the regulatory mechanisms controlling Fas activity, and the expanding recognition of non-apoptotic Fas functions that fundamentally reshape our understanding of this death receptor's biological role.

Molecular Structure and Genomic Organization of the Fas Receptor

Gene Structure and Chromosomal Localization

The human FAS gene spans approximately 25,255 base pairs on the long arm of chromosome 10 at position 10q24.1, organized in a characteristic arrangement of nine protein-encoding exons distributed along the Watson (plus) strand[1][13]. This genomic organization reflects the evolutionary conservation of the TNF receptor superfamily structure, with exons arranged to encode distinct functional domains of the mature receptor protein[1]. The gene demonstrates remarkable evolutionary conservation across mammalian species, with orthologs identified in mice (chromosome 19), primates, and other vertebrates, indicating that the fundamental architecture and biological roles of Fas have been maintained through hundreds of millions of years of evolution[1][14]. Alternative splicing of the FAS transcript represents an important regulatory mechanism, with the most notable variant involving the skipping of exon 6, which encodes the transmembrane domain, resulting in production of a soluble form of Fas (sFas) that functions as a dominant-negative inhibitor by competing with membrane-bound Fas for FasL binding in the extracellular space[33]. This alternative splicing mechanism provides cells with an intrinsic mechanism to modulate their susceptibility to Fas-mediated apoptosis, particularly important in immune cell populations that must balance activation with controlled elimination[33].

Protein Domain Organization and Structural Features

The mature Fas receptor protein comprises 319 amino acids organized into three functionally and structurally distinct domains: an extracellular domain (157 amino acids), a transmembrane domain (17 amino acids), and an intracellular domain (145 amino acids) with predicted molecular weight of 48 kilodaltons[1][13]. The extracellular region, encoded by exons 1 through 5, is characterized by extraordinary richness in cysteine residues (18 cysteines within 157 amino acids), which form disulfide bonds stabilizing a series of cysteine-rich domains (CRDs) that display a characteristic "ladder-like" structure typical of TNF receptor superfamily members[1][3][48]. Specifically, the extracellular domain encompasses three well-structured cysteine-rich domains (CRD1, CRD2, and the upper portion of CRD3), with CRD1 spanning amino acids 56 to 82, stabilized by numerous disulfide bonds that provide structural rigidity and enable specific ligand recognition[48]. Critically, within the first 55 amino acids preceding CRD1 exists a flexible, intrinsically disordered region that contains the pre-ligand assembly domain (PLAD), a region essential for the constitutive oligomerization of Fas molecules even in the absence of ligand binding[14][48]. The PLAD spans residues 49 to 82 and contains a minimal domain (residues 59-82) sufficient to mediate homotypic Fas-Fas receptor interactions, enabling receptors to pre-associate on the cell surface in a ligand-independent manner that conditions them for rapid activation upon FasL engagement[3][14].

The transmembrane domain, encoded by exon 6 and consisting of 17 amino acids, exhibits remarkable functional importance beyond simple membrane anchoring. Recent nuclear magnetic resonance spectroscopic studies of the transmembrane region in lipid bilayer-mimicking bicelles revealed that the Fas transmembrane domain forms a specific homotrimeric structure utilizing proline-containing motifs to create optimal packing geometry distinct from classical coiled-coil arrangements observed in solution[8]. This transmembrane trimerization appears directly coupled to apoptotic signaling competence, as cancer-associated and structure-based mutations disrupting the precise three-dimensional packing of the transmembrane helices substantially reduce both trimerization efficiency and apoptosis induction in intact cells[8]. The intracellular region, encoded by exons 7 through 9, contains the crucial death domain (DD) spanning amino acids 210 to 303, an 85-amino acid module homologous to similar domains in other death receptors and serving as the primary platform for recruitment of downstream signaling proteins[3]. This death domain is characterized by a high number of charged amino acids (24 basic and 19 acidic residues), properties that mediate protein-protein interactions essential for death signal transduction[2]. The extreme carboxyl terminus (amino acids 303-319), comprising the final 15 amino acids, represents a functionally mysterious region that can interact with regulatory proteins such as protein tyrosine phosphatase FAP-1 and the scaffolding protein Dlg1, which antagonize Fas-mediated apoptosis through mechanisms remaining incompletely characterized[3].

Ligand Binding and Pre-Ligand Assembly in Fas Activation

The Nature of Fas Ligand and Its Structural Requirements

Fas ligand exists in two primary forms with distinctly different biological consequences: membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL) generated through metalloprotease-mediated ectodomain shedding[34][40][55]. Membrane-bound FasL presents as a multimeric complex of membrane-anchored homotrimeric units, with increasing evidence suggesting that FasL exists as aggregated trimers creating higher-order oligomeric complexes on the cell surface[1][10]. This multivalency of membrane-bound FasL proves absolutely essential for apoptotic signaling, as synthetic monomeric or even simple homotrimeric soluble FasL fails to trigger apoptosis, whereas engineered hexameric forms of FasL robustly induce cell death by clustering six Fas receptors into a signaling-competent complex[10][35]. The soluble form of FasL (sFasL) generated by proteolytic cleavage predominantly exists as a homotrimer, and critically, this trimeric form shows substantially diminished apoptotic capability compared to its membrane-anchored counterpart[40][55]. Instead, sFasL preferentially triggers non-apoptotic signaling pathways by activating a distinct molecular complex designated the motility-inducing signaling complex (MISC) that recruits different adaptor proteins and kinases than the apoptosis-mediating DISC[40][55]. The structural basis for this functional divergence relates to the presence of a "stalk region" in the sFasL molecule that connects the extracellular trimeric ligand head to the membrane anchoring point in mFasL; removal of this stalk region by certain metalloproteases produces a sFasL molecule incapable of triggering apoptosis regardless of its oligomeric status[34][40][55].

Pre-Ligand Receptor Assembly and the PLAD

One of the most profound paradigm shifts in understanding Fas biology involved the recognition that Fas receptor exists as pre-assembled oligomers on the cell surface prior to ligand binding, a property mediated by the pre-ligand assembly domain (PLAD) residing within the extracellular cysteine-rich domain[14][17]. This pre-assembly occurs independently of FasL, with approximately 46% of wild-type Fas molecules existing in oligomeric states (clusters of 2-3 molecules representing 75% of such clusters) in unstimulated cells[8]. Single-molecule microscopy studies employing photoactivated localization microscopy (PALM) combined with photoactivatable green fluorescent protein (PA-GFP) directly visualized these pre-formed Fas receptor assemblies at the plasma membrane, establishing that receptor oligomerization is an intrinsic property of the receptor rather than a ligand-induced phenomenon[8]. The biological significance of PLAD-mediated pre-assembly became apparent when disruption of PLAD-PLAD interactions completely eliminated Fas signaling capacity, despite preservation of ligand binding capability, indicating that pre-assembled trimers create a conformational platform essential for subsequent ligand-induced signaling[14][17][48]. Molecular models reveal that pre-assembled Fas likely exists in anti-parallel dimer or trimer configurations where critical ligand-binding regions are masked by inter-receptor interfaces, creating an inactive state that requires ligand-induced conformational rearrangement to expose the FasL-binding surfaces[48]. Upon binding of multivalent membrane-bound FasL, the ligand trimerizes and links multiple pre-assembled Fas trimers into increasingly large receptor aggregates, with evidence suggesting that a minimum of six Fas receptors (2 Fas trimers) becomes necessary for achieving full signaling competence[10][48].

The Death-Inducing Signaling Complex: Structure and Assembly Mechanism

Molecular Architecture of DISC Assembly

The death-inducing signaling complex represents the proximal signaling platform where Fas oligomerization couples to proteolytic activation of the caspase cascade initiating programmed cell death. Recent cryogenic electron microscopy (cryo-EM) structures have provided unprecedented mechanistic insight into DISC assembly, revealing that Fas and FADD death domains form an asymmetric dodecameric complex composed of seven Fas death domains and five FADD death domains arranged in a distinctive three-layered architecture[10][45]. The upper and middle layers comprise the seven Fas death domains, while the five FADD death domains form the bottom layer, creating a geometry reminiscent of the caspase-2-activating PIDDosome complex[10][45]. This 7:5 stoichiometry appears to represent the physiologically relevant complex under native conditions, though mass spectrometry studies have documented that Fas-FADD complexes can assemble with varying stoichiometries ranging from 5:5 to 7:5 depending on crystallization conditions and protein concentrations, suggesting that the oligomeric state represents an equilibrium process responsive to local protein concentrations and cellular conditions[10][45]. The Fas death domain interaction interfaces display exquisite specificity, with multiple distinct interaction surfaces operating at different stages of complex assembly. Residues within the first 49 amino acids of the Fas death domain (encompassing the pre-ligand assembly domain) mediate crucial homo-oligomerization contacts, while other death domain residues form the primary interface for FADD death domain binding[3].

The assembly process follows an ordered mechanism: upon massive clustering of Fas receptors by membrane-bound FasL, a striking conformational transition occurs where Fas death domains transition from a "closed" conformation (as observed in isolated death domain structures) to an "open" configuration that exposes critical binding surfaces for FADD interaction[11]. This opening mechanism appears coupled to the lateral diffusion and clustering of pre-assembled Fas trimers, whereby the stabilization of these trimers in large aggregates on the membrane provides the mechanical force necessary to induce and stabilize the conformational transitions required for FADD recruitment[10][11]. The opening transition specifically involves a repositioning of helix 6 of the Fas death domain, a structural element that, when mutated to favor the open conformation, actually enhances apoptotic signaling despite potentially destabilizing the closed state, underscoring the biological importance of achieving and maintaining the open conformation for efficient DISC function[3]. Once FADD death domains bind to the open Fas death domain surfaces, they position the death effector domains (DEDs) at the appropriate spatial orientation and density to nucleate the recruitment and subsequent oligomerization of procaspase-8 molecules.

FADD-Mediated Caspase-8 Recruitment and Activation

Fas-associated death domain (FADD) protein, also designated MORT1 (mediator of receptor-induced toxicity 1), serves as the critical adaptor molecule linking Fas death domain signaling to caspase-8 activation[2][5][7]. FADD consists of two functionally distinct domains connected by a flexible linker: an amino-terminal death effector domain (DED) and a carboxyl-terminal death domain (DD) that binds to Fas[3][7]. The death domain of FADD exhibits remarkable flexibility, with amino acid residues at the interface between FADD and Fas showing variability in their exact spatial positioning, a property that may contribute to the dynamic nature of DISC assembly and disassembly[3]. The DED of FADD contains tandemly repeated DED modules (DED1 and DED2) separated by a linker region, creating a structure that closely resembles the similar DED architecture of caspase-8[10][45]. Upon recruitment to the Fas-FADD death domain complex, FADD death effector domains undergo a remarkable conformational transition, assembling into elongated helical filament structures that nucleate the subsequent polymerization of caspase-8 tandem DED molecules[10][45]. These FADD DED filaments, which exhibit near-complete structural overlap with caspase-8 DED filaments when DED1 and DED2 are considered as equivalent structures, appear to serve as a molecular scaffold that promotes both the positioning and the proximity-induced dimerization of caspase-8 zymogens[10][45].

Procaspase-8, the inactive zymogen form of caspase-8 (also designated FLICE for FADD-like IL-1β-converting enzyme), exists as a monomer in the cytosol until recruited into the DISC through its death effector domains[5][10]. The recruitment of multiple procaspase-8 molecules through their DEDs into the FADD DED filament brings multiple procaspase-8 molecules into sufficient proximity that enables autocatalytic activation through intermolecular cleavage[10][45]. Specifically, the enzymatic domain of one procaspase-8 molecule cleaves the activation loop of a proximate procaspase-8 molecule, resulting in removal of the inhibitory prodomain and generation of the active heterodimeric form of caspase-8 composed of a p18 (large) and p10 (small) subunit[1][2]. This proximity-induced or induced-dimerization mechanism of caspase-8 activation represents a fundamental strategy utilized throughout death receptor signaling, wherein the spacing and positioning afforded by adaptor proteins creates the necessary structural framework for catalytic activation of proteases that are otherwise kept inactive through spatial segregation[5][7][10].

Once activated within the DISC, caspase-8 exists in a state of limited activity, constrained by its association with other DISC components and by the limited availability of certain substrates at the DISC locale[2][5]. Active caspase-8 subsequently dissociates from the DISC, translocating into the cytosolic compartment where it gains unrestricted access to its full complement of proteolytic substrates[1][2]. This physical separation between DISC assembly (at the plasma membrane and in endocytic compartments) and the executioner phase of apoptosis (in the cytosol) provides an additional layer of regulatory control, permitting signal amplification and checkpoint control before commitment to complete cellular demolition[1][2][5].

Type I Versus Type II Cell Death Pathways

Differential Utilization of Apoptotic Cascades in Distinct Cell Types

Fas-expressing cells exhibit profound differences in their mechanisms of death in response to FasL stimulation, leading to their classification as either Type I or Type II cells based on whether they require amplification of the caspase cascade through the intrinsic mitochondrial apoptosis pathway[32][35]. Type I cells, exemplified by thymocytes, mature T lymphocytes, and certain transformed cell lines, respond to Fas engagement with robust and rapid caspase-3 and -7 activation that suffices for efficient apoptosis without requiring mitochondrial outer membrane permeabilization (MOMP) or release of cytochrome c[32][35]. In these cells, the amount of caspase-8 activated within the DISC proves sufficient to directly cleave and activate effector caspases (caspase-3 and -7) to levels exceeding the inhibitory capacity of X-chromosome-linked inhibitor of apoptosis protein (XIAP), permitting rapid progression to the executioner phase of apoptosis[32][35]. The rapid kinetics of Type I cell death, often occurring within 2-5 hours of Fas stimulation, reflects both the efficient apoptotic machinery present in these cells and their historical evolutionary role as cells requiring rapid elimination when autoreactive or aberrantly activated[32].

In sharp contrast, Type II cells, including hepatocytes, pancreatic β-cells, and certain fibroblast populations, demonstrate substantially slower kinetics of Fas-induced death, requiring amplification through the intrinsic apoptotic pathway for efficient killing[32][35]. In these cells, the amount of caspase-8 directly activated by the DISC generates insufficient effector caspase activity to overcome XIAP-mediated inhibition, necessitating engagement of the mitochondrial apoptotic program[32][35]. This amplification pathway utilizes the BH3-interacting domain death agonist (Bid), a BH3-only member of the Bcl-2 protein family that exists in an inactive state in resting cells[32][35]. Activated caspase-8 within the DISC cleaves Bid at a specific aspartate residue, generating a truncated fragment (tBid) that inserts into the outer mitochondrial membrane and promotes conformational changes in the pro-apoptotic Bcl-2 family members Bax and Bak, leading to mitochondrial outer membrane permeabilization[32][35]. This permeabilization releases multiple pro-apoptotic factors including cytochrome c, which combines with cytoplasmic Apaf-1 and procaspase-9 to assemble the apoptosome, a macromolecular platform that catalyzes the activation of caspase-9, which in turn cleaves and activates caspase-3 and -7 in a feed-forward manner[5][32][35]. Additionally, mitochondrial permeabilization releases Smac/DIABLO, an antagonist of IAPs, which reduces XIAP-mediated caspase inhibition and further amplifies the caspase cascade[32][35].

The mechanistic basis for Type I versus Type II cell classification appears linked to differential regulation of XIAP protein levels in response to Fas activation. In Type I cells (thymocytes), Fas stimulation triggers rapid proteolytic degradation of XIAP through a caspase-3-dependent mechanism, reducing inhibitory capacity and permitting efficient effector caspase activation[32]. Remarkably, in Type II cells (hepatocytes), the identical caspase-3 activation triggered by Fas stimulation leads to an increase in XIAP protein levels, a seemingly paradoxical effect that reflects differential regulation through distinct post-translational modification pathways dependent on the cell type[32]. This enhanced XIAP levels in Type II cells effectively increases the apoptotic threshold, necessitating the amplification provided by Bid-mediated mitochondrial engagement to achieve sufficient caspase-3/7 activation for cell death[32]. The differential XIAP regulation appears to be a fundamental property distinguishing these cell types, as deletion of Xiap in Bid-deficient Type II cells reverses their resistance to Fas-mediated lethality, restoring death kinetics approaching those of wild-type cells despite the absence of functional Bid protein[32][35].

Tissue-Specific Differences and Physiological Significance

The differential involvement of Type I versus Type II pathways in various tissues reflects their distinct biological roles and the need for tissue-specific regulation of inflammatory responses. The liver demonstrates exceptional sensitivity to Fas-mediated apoptosis, with systemic administration of Fas agonist antibodies triggering fulminant hepatitis and death within hours through massive hepatocyte apoptosis[49][52]. This hepatic sensitivity relates to the tissue's high expression of Fas receptor and the Type II status of hepatocytes, requiring mitochondrial pathway amplification[49][52]. Importantly, the hepatotoxic response to Fas activation appears synergistically enhanced by TNF signaling, wherein low-level TNF exposure sensitizes hepatocytes to Fas-mediated apoptosis through mechanisms involving the activation of stress signaling kinases including JNK, p38, and the transcription factor NF-κB[49]. This TNF-Fas interplay is physiologically relevant to drug-induced liver failure, wherein drugs such as acetaminophen trigger both TNF expression and Fas receptor upregulation, explaining the often catastrophic nature of acute liver failure in some drug overdose situations[49].

The lymphoid organs, particularly the thymus and germinal centers of secondary lymphoid tissues, represent sites where Fas-mediated apoptosis exerts profound regulatory effects on immune development and the resolution of immune responses. In the thymus, Fas/FasL interactions participate in the deletion of autoreactive T cells, although the relative contribution of Fas-mediated death versus other mechanisms remains incompletely understood[5][15]. In the peripheral immune system, Fas-mediated apoptosis plays an essential role in activation-induced cell death (AICD), a mechanism whereby repeated TCR stimulation induces expression of both Fas and FasL on T cells, creating an autocrine/paracrine death signal that terminates immune responses[5][22]. The germinal center reaction, wherein B cells with low-affinity or autoreactive B cell receptors are eliminated through Fas-FasL interactions with CD4+ helper T cells, represents another critical physiological application of Fas-mediated death in maintaining immune tolerance[5][27].

Regulation of Fas Signaling Through Adaptor Proteins and Post-Translational Modifications

The c-FLIP Protein and Bifurcation of Apoptotic Versus Non-Apoptotic Signaling

The cellular FLICE-inhibitory protein (c-FLIP), which exists in both long (c-FLIP_L) and short (c-FLIP_S) isoforms generated through alternative splicing, represents perhaps the most critical endogenous regulator of the balance between Fas-mediated apoptosis and non-apoptotic signaling[5][57]. c-FLIP contains two death effector domains nearly identical to those of caspase-8 and can therefore bind to FADD through DED-DED interactions, competing with caspase-8 for positions within the DISC[5]. The c-FLIP_S isoform, containing only the DEDs without the catalytic domain, functions as a dominant inhibitor of DISC-mediated caspase-8 activation, with overexpression of c-FLIP_S reducing Fas-induced apoptosis by 80-95% depending on the cell type[5][51]. The c-FLIP_L isoform, containing an intact but catalytically inactive caspase-like domain, exhibits more complex effects, retaining the ability to inhibit apoptosis while simultaneously providing a scaffolding platform for recruitment of kinases that mediate non-apoptotic signaling pathways[5][37].

Genetic studies utilizing c-FLIP-deficient mice revealed that this protein possesses critical non-apoptotic functions beyond simple inhibition of caspase-8, as its complete loss causes embryonic lethality phenocopying that observed in caspase-8-deficient mice[5]. This surprising observation indicated that c-FLIP, when not simply inhibiting caspase-8, must serve important roles in promoting non-apoptotic signaling necessary for immune cell development and homeostasis[5]. Selective deletion of c-FLIP in T lymphocytes or fibroblasts paradoxically accelerated Fas-induced apoptosis in these cells, confirming its apoptosis-inhibitory role in isolation[5]. However, deletion of c-FLIP in all tissues produced embryonic lethality associated with defective immune development and impaired NF-κB signaling, indicating its role in supporting non-apoptotic Fas signaling essential for proper immune function[5]. This led to the recognition that the relative abundance of c-FLIP versus caspase-8 recruited into the DISC effectively determines the signaling outcome: high caspase-8 relative to c-FLIP favors apoptosis, whereas high c-FLIP relative to caspase-8 promotes non-apoptotic kinase signaling through mechanisms involving recruitment of RIP, TRAF proteins, and MAP kinases[5][37][57].

Post-Translational Modifications Regulating Fas Signaling

The Fas receptor and its associated signaling machinery are subject to multiple post-translational modifications that fine-tune the balance between apoptotic and non-apoptotic signaling responses. Ubiquitination represents one such modification, with E3 ubiquitin ligases targeting Fas and FADD for polyubiquitin chain formation that can either promote signaling (through non-degradative K63-linked chains) or antagonize signaling (through K48-linked chains promoting proteasomal degradation)[29]. Phosphorylation of Fas and downstream signaling components by various kinases including Src family kinases, Akt, ERK1/2, and JNK modulates DISC formation efficiency and kinase pathway activation[40][57]. Notably, phosphorylation of specific tyrosine residues on Fas can promote the recruitment of SH2-domain-containing proteins including c-yes and Src kinases, directly coupling Fas engagement to non-apoptotic kinase signaling pathways[40].

S-glutathionylation of Fas at cysteine 294 (murine sequence, corresponding to human cysteine residue 295) represents another regulatory modification that markedly promotes Fas receptor aggregation and subsequent caspase-8 activation[3]. This post-translational modification can be reversed by glutaredoxin enzymes, creating a regulatory cycle whereby reactive oxygen species generated during cellular stress enhance Fas signaling capacity through promoting S-glutathionylation, while antioxidant enzymes antagonize this response[3]. This mechanism provides a molecular link between oxidative stress and Fas-mediated apoptosis, with implications for understanding how cells integrate stress signals to make life-death decisions. Interestingly, caspase-8 itself cleaves and inactivates glutaredoxin-1 (Grx1), creating a positive feedback loop wherein Fas activation enhances oxidative conditions that further promote Fas signaling through continued glutathionylation[3].

Internalization and Membrane Trafficking of Fas Receptor Complexes

Following Fas activation, the receptor undergoes rapid internalization through multiple endocytic pathways, with the internalized DISC compartments concentrating around the Golgi apparatus in a polarized distribution distinct from the general plasma membrane endocytic patterns[39]. Fas stimulation preferentially enhances clathrin-independent endocytic pathways, particularly those dependent on Rho GTPases including CDC42, more than classical clathrin-mediated endocytosis[28][39]. This selective enhancement of specific endocytic portals suggests that Fas-activated signaling drives internalization through routes that may spatially segregate the apoptotic DISC from potential inhibitory factors present in early endosomes or at the plasma membrane. Activated caspases associated with the internalized DISC complexes exhibit perinuclear concentration in the vicinity of recycling endosomes around the Golgi region, indicating that the compartmentalization of active caspases to distinct cellular microdomains may contribute to controlled and localized apoptotic signaling[28][39]. The trafficking of GPI-anchored proteins such as CD59 is markedly altered upon Fas stimulation, with rapid internalization and peri-Golgi accumulation that parallels the trafficking of the apoptotic machinery itself, suggesting that Fas-triggered membrane reorganization may facilitate the internalization of specific lipid raft-associated signaling platforms[28][39].

Lipid raft compartmentalization appears to significantly influence Fas signaling outcome, with Fas receptor and its ligand showing enriched localization to cholesterol- and sphingolipid-rich membrane microdomains[42]. The initial clustering of Fas molecules into lipid raft structures upon FasL binding may represent an early organizing event that facilitates DISC assembly by concentrating the necessary signaling components into discrete membrane domains. Soluble FasL, lacking the membrane anchoring and multivalency of membrane-bound FasL, fails to similarly concentrate Fas into rafts and instead promotes the assembly of alternative signaling complexes (MISC) that activate non-apoptotic pathways. This mechanistic distinction between membrane-bound and soluble ligand signaling highlights how the physical organization of signaling components within specialized membrane microdomains fundamentally determines the biological outcome of Fas engagement.

Non-Apoptotic Functions of Fas Receptor Signaling

Discovery and Characterization of Non-Apoptotic Fas Pathways

Contemporaneous with the accumulation of structural and biochemical evidence for the apoptotic function of Fas, numerous observations emerged indicating that Fas can engage additional signaling pathways distinct from the apoptotic cascade[23][37][40][55]. The most direct evidence came from cell populations that proved refractory or resistant to Fas-induced apoptosis despite expressing high levels of functional Fas receptor and intact downstream apoptotic machinery. For instance, Th2 cells exhibit marked resistance to Fas-mediated apoptosis while nonetheless responding to FasL stimulation with activation of NF-κB, enhanced gene expression, and cellular differentiation[37]. Similarly, glioblastoma and other tumor cell lines develop resistance to Fas-induced apoptosis through either mutation of the Fas gene itself or through overexpression of anti-apoptotic proteins, yet these same cells respond to Fas engagement with enhanced migration, invasion, and metastatic dissemination through activation of non-apoptotic kinase cascades[37][40][55].

The molecular basis for non-apoptotic Fas signaling involves an alternative configuration of the Fas signaling complex wherein soluble FasL (rather than membrane-bound FasL) engages the receptor, or wherein sufficient c-FLIP concentration within DISC-like complexes redirects the signaling outcome from caspase-8-mediated apoptosis toward kinase activation[40][55]. Recent studies characterizing this alternative complex designated the motility-inducing signaling complex (MISC) revealed that it completely lacks both FADD and caspase-8 proteins, instead recruiting the Src family kinase c-yes through a mechanism involving elevated intracellular reactive oxygen species (ROS) generated through NADPH oxidase 3[40]. The MISC appears to form primarily in response to soluble FasL stimulation and lacks the adaptor proteins critical for apoptotic signaling, instead assembling kinases and signaling molecules that activate the PI3K/Akt, ERK1/2 MAP kinase, and NF-κB pathways[40][55]. These kinase pathways promote cell survival, proliferation, migration, and inflammatory cytokine production rather than apoptosis, creating a scenario where Fas stimulation can either kill cells or promote their activation and survival depending on the cellular context and the form of FasL encountered[40][55].

Non-Apoptotic Signaling and Immune Function

Recent investigations utilizing mice bearing Fas mutations that specifically block apoptotic signaling while preserving non-apoptotic pathway capacity revealed the critical importance of non-apoptotic Fas functions in immune homeostasis[20]. Studies of patients with autoimmune lymphoproliferative syndrome (ALPS) bearing FAS mutations demonstrated that defective non-apoptotic Fas signaling, independent of apoptosis resistance, contributes to impaired B cell differentiation and germinal center formation[20]. Mechanistically, transient engagement of FAS upon T-dependent B cell activation decreases mTOR activation through a process dependent on caspase-8 and involving nuclear exclusion of PTEN, a critical negative regulator of PI3K signaling[20]. This non-apoptotic mTOR modulation by FAS signaling acts as a molecular switch determining whether activated B cells commit to germinal center differentiation (associated with lower mTOR activity and appropriate transcriptional programs) versus extrafollicular differentiation producing short-lived plasma cells with impaired antibody affinity maturation[20]. In B cells from ALPS-FAS patients, the defect in FASL-mediated PTEN nuclear exclusion and mTOR inhibition correlates with expansion of extrafollicular B cell responses and reduced germinal center formation, despite intact apoptotic resistance[20]. This finding reveals that non-apoptotic Fas signaling provides essential instructions for proper immune development independent of its death-inducing capacity.

The role of non-apoptotic Fas signaling in regulating Th2-mediated inflammation further exemplifies the importance of these alternative pathways[37]. In allergic airway inflammation models, Fas-deficiency on T cells delays resolution of type 2 inflammation and eosinophilia, but this defect cannot be overcome by increasing T cell survival through deletion of pro-apoptotic molecules (Bim) or overexpression of anti-apoptotic molecules (Bcl-xL)[37]. Instead, using mice bearing Fas mutations that specifically ablate apoptotic signaling while preserving non-apoptotic functions, investigators demonstrated that non-apoptotic Fas signaling in Th2 cells drives resolution of inflammation[37]. This non-apoptotic signaling, occurring specifically in Th2 cells which exhibit inherent resistance to Fas-induced apoptosis and preferentially activate NF-κB upon FasL exposure, appears critical for implementing the transcriptional and functional changes necessary for inflammation resolution[37]. These findings suggest that Fas may function in distinct cellular contexts as either a death receptor (in type I cells) or as an activating receptor promoting cellular processes essential for immune homeostasis (in apoptosis-resistant cell populations).

Non-Apoptotic Fas Signaling in Cell Migration and Metastasis

The soluble form of FasL detected in serum of patients with aggressive solid tumors, particularly triple-negative breast cancer, colon cancer, and ovarian cancer, activates non-apoptotic signaling pathways that enhance tumor cell migration, invasion, and metastatic dissemination[40][55]. The MISC complex assembled in response to sFasL stimulation recruits Src family kinases and promotes phospholipase C-γ1 (PLC-γ1) activation, generating inositol 1,4,5-trisphosphate (IP3) and diacylglycerol that trigger intracellular calcium mobilization and protein kinase C activation[40][56]. These signaling cascades, collectively termed calcium-dependent signaling, promote cell migration, focal adhesion dynamics, and cytoskeletal rearrangement necessary for metastatic dissemination[40][56]. The elevated plasmin levels in the tumor microenvironment of solid tumors creates a particularly hostile context for immune cell killing, as plasmin proteolytically cleaves human FasL at a unique cleavage site created by a single evolutionary amino acid change (serine at position 153 instead of proline, unique to humans compared to non-human primates) that renders human FasL uniquely susceptible to plasmin-mediated inactivation[44]. This evolutionary vulnerability in human FasL, apparently selected for in our species to enhance neural development, creates a substantial disadvantage in immune surveillance against plasmin-expressing solid tumors, explaining the frequent failure of CAR-T and other T cell immunotherapies in solid tumors despite their efficacy in blood cancers lacking plasmin expression[44].

Clinical Manifestations of Fas Dysfunction: Autoimmune Lymphoproliferative Syndrome

Molecular Basis of ALPS Pathogenesis

Autoimmune lymphoproliferative syndrome (ALPS) represents a rare but clinically significant genetic disorder caused by germline mutations affecting Fas-mediated apoptosis[21][24][47]. Most ALPS patients carry heterozygous missense mutations in the FAS gene that encode defective Fas proteins exhibiting dominant-negative effects on wild-type Fas signaling[47]. The disease manifests with characteristic clinical features including early-onset lymphadenopathy (often presenting in childhood), splenomegaly, immune cytopenias (low blood counts due to autoimmune destruction), and significantly elevated risk for B cell lymphomas, reflecting the loss of Fas-mediated elimination of autoreactive lymphocytes and impaired immune homeostasis[21][24][47]. The hallmark lymphoproliferative phenotype involves massive expansion of CD4-CD8- double-negative (DN) T cells expressing the B cell marker B220, creating a distinctive circulating population of unusual T cells not present in healthy individuals[21][38][47].

The molecular mechanisms by which FAS mutations cause ALPS demonstrate remarkable diversity despite the unified clinical phenotype[47]. Mutations affecting the extracellular domain of Fas frequently result in reduced surface expression of the receptor through nonsense-mediated decay of the mutant transcript or proteasomal degradation of the misfolded protein, a mechanism termed haploinsufficiency[47]. These extracellular-region mutations attenuate DISC formation and apoptosis signaling to a lesser extent than intracellular domain mutations, and notably, patients with haploinsufficient FAS mutations show a lower penetrance of clinical symptoms and, strikingly, have not developed lymphomas despite decades of observation, in contrast to patients bearing intracellular domain mutations who frequently develop lymphomas[47]. This observation suggests that residual Fas function, even when reduced to 50% of normal levels through haploinsufficiency, may suffice for tumor surveillance function. Mutations affecting the intracellular death domain generally produce dominant-negative effects wherein the defective Fas protein interferes with signaling even from wild-type Fas on the same cell[47]. These intracellular mutations typically prevent recruitment of FADD or cause instability of the DISC complex, demonstrating the critical importance of death domain integrity for Fas signaling[7][47].

Pathogenesis of Lymphoproliferation and Autoimmunity

The expansion of double-negative T cells in ALPS represents an enigmatic aspect of the disease, as these unusual cells rarely develop in healthy individuals yet proliferate massively when Fas is defective[38]. Recent investigations revealed that dysregulated expression of Eomesodermin (Eomes), a T-box transcription factor critical for effector and memory CD8+ T cell function, characterizes DN T cells in both ALPS mice (lpr mice) and ALPS patients[38]. T cell-specific deletion of Eomes substantially ameliorated the DN T cell expansion and lymphoproliferation of ALPS mice, establishing Eomes dysregulation as essential for DN T cell pathogenesis[38]. However, residual lymphoproliferation persisted in ALPS mice lacking T cell Eomes, indicating that additional Fas-dependent mechanisms beyond Eomes-regulated DN T cell expansion contribute to the overall lymphoproliferative phenotype[38]. The expansion of DN T cells, while dramatic, appears less important than B cell dysfunction for driving the autoimmune manifestations of ALPS, as selective deletion of Fas from B cells or antigen-presenting cells suffices to reproduce the autoimmune phenotype of systemic ALPS[19][27].

Investigations of Fas-mediated control of antigen-presenting cells (APCs) revealed that mature antigen-presenting cells, particularly dendritic cells, express elevated levels of Fas receptor following exposure to microbial stimuli, predisposing them to Fas-mediated death by activated T cells[19]. The elimination of Fas-positive antigen-presenting cells by T cells bearing FasL represents a negative feedback mechanism that terminates immune responses by destroying the cells presenting antigenic stimuli[19]. Tissue-specific deletion of Fas in dendritic cells proved sufficient to cause systemic autoimmunity and lymphoproliferation, establishing that Fas-mediated elimination of activated antigen-presenting cells represents a critical control mechanism preventing persistent activation of self-reactive T cells[19]. Similarly, deletion of Fas specifically from B cells resulted in their accumulation and systemic autoimmunity characterized by elevated autoantibodies and immune complex deposition[19][27]. The B cell-intrinsic defect in ALPS appears to involve both failure of Fas-mediated elimination of low-affinity and autoreactive B cells within germinal centers and defective generation of memory B cells, reflecting both apoptotic and non-apoptotic functions of Fas in B cell physiology[20][27].

Evolutionary Significance and Comparative Biology of Fas

Conservation and Evolutionary Divergence

The Fas receptor belongs to an evolutionarily ancient signaling system, with orthologs identified throughout vertebrate species and even invertebrate organisms, indicative of its fundamental importance in organismal biology[43][46]. Molecular phylogenetic analysis of death receptors including Fas, TNFR1, DR3, DR4, DR5, and DR6 revealed that Fas represents a somewhat divergent member of the TNF receptor family, having evolved from a common ancestor with TNFR family members more than 500 million years ago, before the radiation of modern animal phyla[43][46]. Despite this evolutionary distance, Fas maintains the characteristic structural organization of TNF receptors, including the cysteine-rich extracellular domains with their disulfide-bonded ladder-like architecture and the intracellular death domain critical for signaling[43][46]. The strong conservation of specific cysteine residues throughout the extracellular domain across diverse species suggests that these residues provide essential structural constraints maintaining the overall three-dimensional organization necessary for ligand binding and receptor activation[43]. Notably, more amino acid residues exhibit conservation in TNFR1, DR3, and TNFBR compared to Fas (16 highly conserved residues in TNFR1, DR3, TNFBR versus only 7 in Fas), suggesting that Fas may be more permissive of sequence variation while maintaining overall functional capacity, or alternatively, that Fas evolved more rapidly following its divergence from common ancestors.

Evolutionary Trade-offs: Human FasL Vulnerability to Plasmin

A striking and evolutionarily significant finding emerged from comparative analysis of Fas ligand sequences across primates and humans[44]. Humans possess a unique evolutionary substitution in the FasL protein at position 153, where a proline residue present in all non-human primates (including chimpanzees) is replaced with serine in humans[44]. This single-residue change creates a novel proteolytic cleavage site for plasmin, a serine protease frequently elevated in aggressive solid tumors that are heavily dependent on this enzyme for metastasis[44]. The consequence of this human-specific mutation appears paradoxical: while it may have contributed to the evolutionary expansion of the human cerebral cortex (perhaps through effects on neural development), it simultaneously renders human FasL extremely vulnerable to proteolytic inactivation by plasmin in the tumor microenvironment of solid malignancies[44]. In vitro experiments demonstrated that human FasL is cleaved and inactivated by plasmin with high efficiency, rendering immune cells unable to trigger apoptosis in tumor cells even when properly activated and armed with FasL molecules[44]. Remarkably, non-human primates such as chimpanzees exhibit much lower rates of solid tumors compared to humans, a difference that may partially reflect this evolutionary vulnerability in human FasL to plasmin-mediated inactivation in tumor environments[44].

This discovery has direct implications for cancer immunotherapy, providing a mechanistic explanation for the frequent failure of CAR-T and T cell-based therapies against solid tumors while these same approaches show substantial efficacy against blood cancers that typically do not express high levels of plasmin[44]. The differential dependence of blood cancers versus solid tumors on plasmin-mediated proteolysis and matrix degradation creates an environment wherein human immune cells' primary death-inducing weapon (FasL) becomes disabled specifically in solid tumor contexts[44]. Blocking plasmin or engineering protective antibodies that shield FasL from plasmin cleavage restored apoptosis-inducing capacity in in vitro experiments, suggesting that combination approaches combining anti-plasmin strategies with FasL-based or T cell immunotherapies may enhance efficacy against solid tumors[44]. This example illustrates how evolutionary changes in immune molecules, apparently selected for beneficial effects on neural development, can create substantial vulnerabilities to modern age-related diseases not encountered in our evolutionary history.

Integration of Signaling Pathways: Type I and Type II Mechanisms Revisited

Recent Structural Insights into DISC Assembly and Signaling Amplification

The latest cryo-EM structures of the Fas-FADD complex, published in 2024, provide unprecedented mechanistic clarity regarding how the asymmetric 7:5 oligomeric architecture translates receptor clustering into caspase-8 activation and apoptotic signal amplification[10][45]. The structural analysis reveals that the FADD death effector domains emanating from the bottom layer of the complex form extended filamentous structures that closely resemble the native architecture of caspase-8 tandem DED filaments[10][45]. This structural similarity is not coincidental but appears essential for the mechanism of caspase-8 assembly and activation, as FADD DED filaments effectively serve as nucleation scaffolds that promote the polymerization of caspase-8 tandem DED domains into similar helical structures[10][45]. The hypothesis emerging from this structural work proposes that FADD DED filaments lower the kinetic barrier for caspase-8 tandem DED assembly by providing a pre-organized template of charged and hydrophilic residues that precisely match those required for productive caspase-8 DED-DED interactions[10][45]. Three distinct DED interface types (Type I hydrophobic, Type II and III hydrophilic/charged) mediate both FADD-FADD interactions within the filament and FADD-caspase-8 interactions, with the electrostatic properties of FADD DED closely resembling those of individual caspase-8 DED domains, enabling seamless integration of caspase-8 molecules into the growing FADD filament[10][45].

This structural mechanism of signal amplification through filamentous assembly explains several previously enigmatic observations. The requirement for hexameric (or higher-order oligomeric) FasL to trigger apoptosis, despite the trimeric nature of individual FasL molecules, now appears to reflect the need to cluster sufficient numbers of Fas receptors to achieve the critical density of Fas death domains required to form the minimal signaling-competent oligomeric platform[10][45]. The dodecameric 7:5 complex may represent one such minimal unit, though higher-order clustering likely generates additional complexes that further amplify signaling through positive feedback mechanisms. The proline-containing sequences in the Fas transmembrane domain create optimal packing geometry for trimerization, and the precise spatial organization of these transmembrane trimers appears essential for communicating the conformational changes induced by extracellular ligand binding down to the intracellular death domains, enabling the opening transitions necessary for FADD recruitment[8][10].

Differential Regulation of Apoptosis in Type I and Type II Cells: Molecular Mechanisms

The emerging understanding of how Type I and Type II cell classification relates to XIAP abundance and regulation provides a molecular explanation for the differential kinetics of Fas-induced apoptosis in various cell types[32][35]. Recent mechanistic studies indicate that the key decision point determining whether a cell exhibits Type I or Type II signaling relates to the ability of activated caspase-3 (itself a product of the initial caspase-8 activation) to trigger the degradation of XIAP protein[32]. In Type I cells such as thymocytes, the caspase-8 levels activated within the DISC prove sufficient to directly cleave and activate caspase-3 to concentrations that exceed XIAP inhibitory capacity; additionally, activated caspase-3 directly cleaves and destroys XIAP, creating a positive feedback loop that ensures complete apoptotic commitment[32]. In Type II cells including hepatocytes, the initial caspase-8 and caspase-3 activation is more modest, allowing XIAP to maintain inhibitory control; however, the same activated caspase-3 that is inhibited by XIAP in the initial phase somehow promotes XIAP upregulation through unknown post-translational mechanisms, perhaps involving altered ubiquitination or phosphorylation of XIAP or its regulatory proteins[32][35]. This elevated XIAP then effectively increases the apoptotic threshold for Type II cells, forcing them to engage the Bid-BaxBak-mitochondrial pathway amplification mechanism[32][35].

Remarkably, administration of SMAC mimetics, which antagonize IAP proteins and mimic Smac/DIABLO released from mitochondria, can reverse the resistance of Bid-deficient Type II cells to Fas-induced apoptosis, restoring death kinetics approaching those of wild-type cells[32]. This observation indicates that the Caspase-XIAP-Smac axis forms a central regulatory nexus in Fas-mediated apoptosis, with the relative abundances and activities of these molecules determining the cellular response[32]. The Type II pathway may represent an evolutionary strategy for tissues such as the liver that require heightened apoptotic thresholds to prevent inadvertent death from basal activation of death receptors and stress signals, while Type I cells such as lymphocytes represent cell types where rapid elimination upon activation or autoreactivity proves paramount to immune homeostasis.

Tissue-Specific Expression and Physiological Functions

Fas Expression Patterns in Embryonic Development and Adult Tissues

Comprehensive analysis of Fas and FasL expression during murine embryonic development revealed that Fas expression becomes detectable in distinct cell types of developing tissues from embryonic day 16.5 onwards, with particular prominence in developing sinusoid endothelium, thymic primordium, lung, and liver[15]. FasL expression during embryogenesis, in contrast, shows much more restricted distribution, primarily detected in submaxillary gland epithelial cells and the developing nervous system[15]. This spatial and temporal separation of Fas and FasL expression during development suggests that embryonic Fas/FasL interactions, while demonstrating significant expression in some tissues, may not be primarily responsible for the programmed cell death events characteristic of neural development, tissue remodeling, and organ formation during embryogenesis[15]. This finding contrasts with the substantial expression observed in adult tissues and suggests that the Fas system acquires greater importance in adult tissues than in embryonic development.

In adult tissues, remarkably wide expression of both Fas and FasL has been documented through sensitive RNase protection assays, with constitutive coexpression noted in thymus, lung, spleen, small intestine, large intestine, seminal vesicles, prostate, and uterus[15]. Tissues exhibiting the highest coexpression of Fas and FasL generally are characterized by rapid apoptotic cell turnover and active cell proliferation, consistent with a role for Fas-FasL interactions in regulating physiological cell turnover[15]. Tissues expressing FasL are notably enriched for immune-privileged sites including eye, brain, placenta, and testis, tissues that must actively protect their resident cells from immune attack through various mechanisms, with FasL expression on specialized cell types within these tissues triggering apoptosis of infiltrating lymphocytes bearing Fas receptor[15][18]. The cardiac expression of FasL, normally absent or minimal in wild-type hearts, becomes pathogenic when artificially enforced through transgenic expression, triggering a proinflammatory response characterized by mild leukocyte infiltration, interstitial fibrosis, and concentric cardiac hypertrophy, demonstrating that FasL expression in cardiac myocytes can actively drive pathological inflammation despite the coexpression of Fas in these cells[18].

Conclusion: Fas as a Central Regulatory Hub in Immune Homeostasis and Cellular Death

The Fas receptor emerges from decades of intensive investigation as far more than a simple death-inducing receptor, representing instead a sophisticated molecular platform integrating apoptotic and non-apoptotic signaling capable of flexibly responding to diverse cellular contexts and external signals. The structural advances achieved through cryo-EM analysis of the DISC complex have unveiled how massive clustering of pre-assembled Fas receptor trimers couples to formation of asymmetric oligomeric death domain platforms that nucleate caspase-8 activation through FADD-mediated DED filament assembly and polymerization. The recognition that Fas signaling outcome depends critically on ligand form (membrane-bound versus soluble), receptor oligomerization state, adaptor protein composition, and post-translational modifications has revealed a far more nuanced picture than the simple binary "live or die" model that dominated earlier understanding. The dramatic tissue-specific differences in apoptotic pathway utilization, exemplified by Type I and Type II cells, reflect elegant regulatory mechanisms wherein XIAP levels and regulation create different apoptotic thresholds appropriate for distinct tissue functions. The non-apoptotic functions of Fas—ranging from regulating mTOR-dependent B cell fate decisions to promoting immune cell migration and inflammation resolution—have emerged as equally critical to organismal biology, suggesting that the name "death receptor" substantially underestimates the biological complexity of this molecule.

The clinical importance of Fas dysfunction extends beyond the relatively rare ALPS syndrome to encompass the majority of human cancers, which frequently upregulate anti-apoptotic mechanisms countering Fas signaling, and to autoimmune diseases including systemic lupus erythematosus and various vasculitides, where soluble FasL and defective Fas signaling promote pathological inflammation[40][55]. The evolutionary history of human FasL, wherein a single amino acid change apparently selected for neural development created a vulnerability to plasmin-mediated inactivation in solid tumors, exemplifies how evolutionary trade-offs can create unexpected vulnerabilities to modern diseases. Future therapeutic strategies targeting Fas signaling must account for the tissue-specific roles of apoptotic versus non-apoptotic pathways, the impact of soluble versus membrane-bound ligand forms, and the complex regulation of adaptor proteins and post-translational modifications that determine signaling outcome. The convergence of structural biology, evolutionary analysis, and clinical investigation on the Fas system continues to yield insights into fundamental mechanisms of programmed cell death while revealing previously unsuspected roles in immune regulation, development, and disease pathogenesis.

Citations

https://en.wikipedia.org/wiki/Fas_receptor
https://www.ncbi.nlm.nih.gov/books/NBK6345/
https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.00314/full
https://www.ncbi.nlm.nih.gov/gene/355
https://pmc.ncbi.nlm.nih.gov/articles/PMC2956119/
https://pubmed.ncbi.nlm.nih.gov/25153377/
https://pubmed.ncbi.nlm.nih.gov/20935634/
https://pmc.ncbi.nlm.nih.gov/articles/PMC4761300/
https://pubmed.ncbi.nlm.nih.gov/11525634/
https://www.pnas.org/doi/10.1073/pnas.2504819122
https://pmc.ncbi.nlm.nih.gov/articles/PMC2788920/
https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2018.00101/full
https://pubmed.ncbi.nlm.nih.gov/17449269/
https://pmc.ncbi.nlm.nih.gov/articles/PMC2120795/
https://geneglobe.qiagen.com/us/knowledge/gene/ENSG00000026103
https://www.science.org/doi/10.1126/science.288.5475.2328
https://www.jci.org/articles/view/8212
https://pmc.ncbi.nlm.nih.gov/articles/PMC2575811/
https://www.science.org/doi/10.1126/sciimmunol.adj5948
https://primaryimmune.org/understanding-primary-immunodeficiency/types-of-pi/autoimmune-lymphoproliferative-syndrome-alps
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00237/full
https://pubmed.ncbi.nlm.nih.gov/12485619/
https://ashpublications.org/blood/article/123/13/1989/32605/Natural-history-of-autoimmune-lymphoproliferative
https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.631274/full
https://rupress.org/jcb/article/218/6/1776/61850/Post-translational-regulation-of-ubiquitin
https://pmc.ncbi.nlm.nih.gov/articles/PMC3470429/
https://pmc.ncbi.nlm.nih.gov/articles/PMC2626565/
https://pmc.ncbi.nlm.nih.gov/articles/PMC8946176/
https://med.stanford.edu/content/dam/sm/shared/community/department-of-medicine/Immuno/JournalClub/19-20/JC-week-11_Hunter.pdf
https://pmc.ncbi.nlm.nih.gov/articles/PMC7112278/
https://academic.oup.com/jmcb/article/2/2/63/894704
https://elifesciences.org/articles/80953
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1074099/full
https://pmc.ncbi.nlm.nih.gov/articles/PMC3252833/
https://pmc.ncbi.nlm.nih.gov/articles/PMC7772363/
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.02521/full
https://pmc.ncbi.nlm.nih.gov/articles/PMC2997140/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5623854/
https://ashpublications.org/bloodict/article-split/1/3/100010/547286/Lipid-nanoparticle-Fas-gene-therapy-suppresses
https://ashpublications.org/blood/article-abstract/107/6/2384/22094/Fas-ligand-is-localized-to-membrane-rafts-where-it
https://pmc.ncbi.nlm.nih.gov/articles/PMC3964250/
https://www.sciencedaily.com/releases/2025/07/250702214136.htm
https://journals.biologists.com/jcs/article/129/1/108/138738/Evolutionarily-conserved-primary-TNF-sequences
https://pmc.ncbi.nlm.nih.gov/articles/PMC3725553/
https://pmc.ncbi.nlm.nih.gov/articles/PMC12432253/
https://www.jci.org/articles/view/42686
https://pmc.ncbi.nlm.nih.gov/articles/PMC11049660/
https://haematologica.org/article/view/4668
https://pmc.ncbi.nlm.nih.gov/articles/PMC3228663/
https://pmc.ncbi.nlm.nih.gov/articles/PMC1523423/
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https://pmc.ncbi.nlm.nih.gov/articles/PMC2933433/
https://www.thermofisher.com/us/en/home/life-science/antibodies/antibodies-learning-center/antibodies-resource-library/cell-signaling-pathways/fas-signaling-pathway.html
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https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0031258

Notes

(FAS-notes.md)

FAS (CD95/APO-1) Notes - ISOFORMS Project

Key Isoform Biology

FAS is a classic example of antagonistic membrane vs soluble isoforms.

Isoforms (7 named)

Isoform	UniProt ID	Synonym	Key Feature	Function
Isoform 1	P25445-1	-	Full-length, membrane-bound	INDUCES APOPTOSIS
Isoform 2	P25445-2	del2, D	Lacks exons	Soluble, blocks apoptosis
Isoform 3	P25445-3	del3, E	Lacks exons	Soluble, blocks apoptosis
Isoform 4	P25445-4	B	-	Soluble, blocks apoptosis
Isoform 5	P25445-5	C	-	Soluble, blocks apoptosis
Isoform 6	P25445-6	TMdel, A	Lacks TM domain	Soluble, BLOCKS APOPTOSIS
Isoform 7	P25445-7	FasExo8Del	-	Unknown

Critical Antagonism: Membrane vs Soluble

Membrane-bound FAS (Isoform 1):
- Contains transmembrane domain
- Forms DISC (Death-Inducing Signaling Complex)
- Recruits FADD and CASP8
- TRIGGERS APOPTOSIS

Soluble FAS (Isoforms 2-6):
UniProt states:

"The secreted isoforms 2 to 6 block apoptosis (in vitro)"

Mechanism: Soluble FAS acts as a decoy receptor, binding FasL without triggering apoptosis.

Tissue-Specific Expression (UniProt)

"Isoform 1 and isoform 6 are expressed at equal levels in resting peripheral blood mononuclear cells. After activation there is an increase in isoform 1 and decrease in the levels of isoform 6."

This suggests splicing regulation shifts towards the pro-apoptotic membrane form upon immune activation.

GOA Annotation Status

96 total annotations
NO isoform-specific annotations (no P25445-X identifiers)
All apoptosis annotations likely refer to membrane-bound isoform 1

Expected Annotation Issues

"Positive regulation of apoptotic process" - TRUE for isoform 1, FALSE for isoforms 2-6
"Negative regulation of apoptotic process" - should be annotated for soluble isoforms!
Death domain - present in all, but only functional in membrane form

Key References

PMID:7533181, PMID:9184224 - Soluble FAS blocks apoptosis
PMID:7575433 - Isoform expression patterns

📄 View Raw YAML

id: P25445
gene_symbol: FAS
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'FAS (CD95/APO-1) is a death receptor that triggers extrinsic apoptosis.
  CRITICAL ISOFORM BIOLOGY: Alternative splicing produces 7 isoforms with ANTAGONISTIC
  functions: (1) Membrane-bound isoform 1 (P25445-1) forms the DISC with FADD and
  CASP8 to trigger apoptosis; (2) Soluble isoforms 2-6 (lacking transmembrane domain)
  act as DECOY RECEPTORS that BLOCK apoptosis by binding FasL without signaling. UniProt
  states "The secreted isoforms 2 to 6 block apoptosis (in vitro)". The GOA has BOTH
  GO:0043065 (positive regulation) AND GO:0043066 (negative regulation) of apoptosis
  - this reflects isoform conflation where membrane and soluble forms have opposite
  effects.'
existing_annotations:
  - term:
      id: GO:0005031
      label: tumor necrosis factor receptor activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'CORE FUNCTION of FAS. FAS/CD95 is a type I transmembrane death receptor
        that binds FASLG (FasL/CD95L) and mediates apoptotic signaling. FAS is a bona
        fide member of the TNF receptor superfamily (TNFRSF6), containing three cysteine-rich
        domains (CRDs) in its extracellular region characteristic of this family [PMID:1375228].
        Note: This annotation applies primarily to membrane-bound isoform 1 (P25445-1);
        soluble isoforms retain ligand binding but lack signaling capacity.'
      action: ACCEPT
      reason: This is a core molecular function of FAS. The deep research 
        confirms FAS is TNFRSF6 with characteristic cysteine-rich domains that 
        mediate FasL binding. IBA inference is appropriate as this function is 
        highly conserved across the TNFR family.
      supported_by:
        - reference_id: PMID:1375228
          supporting_text: The deduced amino acid sequence of APO-1 showed 
            sequence identity with the Fas antigen, a cysteine-rich 
            transmembrane protein of 335 amino acids with significant similarity
            to the members of the tumor necrosis factor/nerve growth factor 
            receptor superfamily.
        - reference_id: file:human/FAS/FAS-deep-research-perplexity.md
          supporting_text: 'provider: perplexity'
  - term:
      id: GO:0045121
      label: membrane raft
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS localizes 
        to cholesterol- and sphingolipid-rich membrane rafts, which is important
        for efficient DISC assembly and apoptotic signaling. Caveolin-1 
        regulates Fas localization and DISC formation in membrane rafts 
        [PMID:21382479]. The deep research confirms membrane raft localization 
        facilitates FAS clustering upon FasL binding.
      action: ACCEPT
      reason: 'Well-supported localization for membrane-bound FAS isoform 1. IBA inference
        is consistent with direct experimental evidence (IDA PMID:21382479). Note:
        Does not apply to soluble isoforms 2-6 which are secreted.'
      supported_by:
        - reference_id: PMID:21382479
          supporting_text: We found that Cav-1 regulated Fas signaling and 
            mediated the communication between extrinsic and intrinsic pathways.
            Shortly after hyperoxia (4 h), the colocalization and interaction of
            Cav-1 and Fas increased, followed by Fas multimer and DISC 
            formation.
  - term:
      id: GO:0009897
      label: external side of plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). The 
        extracellular domain of membrane-bound FAS is exposed on the external 
        side of the plasma membrane where it binds FasL. FAS is a type I 
        transmembrane protein with the N-terminal CRD-containing ligand-binding 
        domain facing the extracellular space [PMID:1375228].
      action: ACCEPT
      reason: 'Correct localization for the canonical membrane-bound isoform 1. This
        is essential for FasL binding and receptor function. Note: Soluble isoforms
        2-6 are secreted and do not have this localization.'
      supported_by:
        - reference_id: PMID:1375228
          supporting_text: The APO-1 antigen as defined by the mouse monoclonal 
            antibody anti-APO-1 was previously found to be expressed on the cell
            surface of activated human T and B lymphocytes and a variety of 
            malignant human lymphoid cell lines.
  - term:
      id: GO:0006924
      label: activation-induced cell death of T cells
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CORE FUNCTION of membrane-bound FAS. Activation-induced cell 
        death (AICD) is a critical mechanism for T cell homeostasis where 
        repeated TCR stimulation induces FAS and FasL expression, creating an 
        autocrine/paracrine death signal that terminates immune responses. The 
        deep research (FAS-deep-research-perplexity.md) confirms FAS-FasL 
        interactions participate in AICD of mature T-cells.
      action: ACCEPT
      reason: Well-established core function of FAS in immune regulation. AICD 
        via FAS-FasL is essential for peripheral tolerance and termination of 
        immune responses. Defects in this pathway cause ALPS (autoimmune 
        lymphoproliferative syndrome).
      supported_by:
        - reference_id: PMID:7538907
          supporting_text: Overexpression of FADD in MCF7 and BJAB cells induces
            apoptosis, which, like Fas-induced apoptosis, is blocked by CrmA, a 
            specific inhibitor of the interleukin-1 beta-converting enzyme.
  - term:
      id: GO:0031265
      label: CD95 death-inducing signaling complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS is a core 
        component of the CD95 death-inducing signaling complex (DISC), which 
        forms upon FasL binding and consists of FAS, FADD, and procaspase-8. The
        Fas-FADD death domain complex forms an asymmetric oligomeric structure 
        of 5-7 Fas DD and 5 FADD DD [PMID:20935634]. This is the defining 
        functional complex for FAS-mediated apoptosis.
      action: ACCEPT
      reason: 'DISC localization is the core functional context for membrane-bound
        FAS. Structural studies confirm the oligomeric Fas-FADD complex architecture.
        Note: Soluble FAS isoforms cannot form DISC as they lack the transmembrane
        domain needed for membrane anchoring and proper DISC assembly.'
      supported_by:
        - reference_id: PMID:20935634
          supporting_text: The death-inducing signaling complex (DISC) formed by
            the death receptor Fas, the adaptor protein FADD and caspase-8 
            mediates the extrinsic apoptotic program
  - term:
      id: GO:0032872
      label: regulation of stress-activated MAPK cascade
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: FAS ligation activates stress-activated protein kinases including
        ASK1 and JNK/SAPK under certain conditions, particularly glutamine 
        deprivation [PMID:11096076]. This represents a non-apoptotic signaling 
        output of FAS activation that can modulate cellular stress responses.
      action: KEEP_AS_NON_CORE
      reason: FAS can regulate MAPK cascades but this is not its primary 
        function. The deep research confirms non-apoptotic signaling pathways 
        exist but the core function remains apoptosis induction. This annotation
        reflects ancillary signaling.
      supported_by:
        - reference_id: PMID:11096076
          supporting_text: Fas ligation activated apoptosis signal-regulating 
            kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK; also known as 
            stress-activated protein kinase (SAPK)) in Gln-deprived cells
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ISOFORM-SPECIFIC annotation for SOLUBLE FAS isoforms (P25445-2 to
        P25445-6). Soluble FAS isoforms lacking the transmembrane domain act as 
        decoy receptors that bind FasL and block apoptosis. This is the OPPOSITE
        function of membrane-bound isoform 1. PMID:7510905 demonstrates soluble 
        FAS blocks Fas-mediated apoptosis.
      action: ACCEPT
      reason: Correct annotation but ONLY for soluble isoforms 2-6. UniProt 
        explicitly states that secreted isoforms 2 to 6 block apoptosis in 
        vitro. This IBA annotation likely reflects phylogenetic inference that 
        includes soluble forms.
      supported_by:
        - reference_id: PMID:7510905
          supporting_text: Supernatants from cells transfected with the variant 
            messenger RNA blocked apoptosis induced by the antibody to Fas
  - term:
      id: GO:0097049
      label: motor neuron apoptotic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: FAS can mediate motor neuron apoptosis. The deep research 
        mentions FAS expression in the developing nervous system and its role in
        neuronal cell death. However, this represents a tissue-specific 
        manifestation of FAS apoptotic function rather than a distinct 
        mechanism.
      action: KEEP_AS_NON_CORE
      reason: While FAS can mediate motor neuron apoptosis, this is a 
        context-specific application of its general apoptotic function. The core
        function is death receptor activity and apoptosis induction, which 
        applies across cell types. Motor neuron apoptosis is one of many 
        cellular contexts where FAS functions.
      supported_by:
        - reference_id: PMID:7538907
          supporting_text: Overexpression of FADD in MCF7 and BJAB cells induces
            apoptosis, which, like Fas-induced apoptosis, is blocked by CrmA
  - term:
      id: GO:0097527
      label: necroptotic signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: FAS can trigger necroptotic cell death through RIP1 (RIPK1) when 
        caspase activity is inhibited. FAS interacts with RIP1 via death domain 
        interactions [PMID:7538908]. RIP-mediated necrosis involves inhibition 
        of ADP/ATP exchange [PMID:16507998]. This represents an alternative cell
        death pathway downstream of FAS activation.
      action: KEEP_AS_NON_CORE
      reason: Necroptosis is a secondary pathway activated when apoptosis is 
        blocked. The primary function of FAS is apoptosis induction; necroptosis
        occurs under specific conditions (caspase inhibition). This is a valid 
        but non-core function.
      supported_by:
        - reference_id: PMID:7538908
          supporting_text: 'Using a genetic selection based on protein-protein interaction
            in yeast, we have identified two gene products that associate with the
            intracellular domain of Fas: Fas itself, and a novel 74 kDa protein we
            have named RIP'
  - term:
      id: GO:0033209
      label: tumor necrosis factor-mediated signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: FAS is a member of the TNF receptor superfamily (TNFRSF6) and 
        mediates signaling analogous to other TNFR family members. However, FAS 
        specifically responds to FasL (FASLG/TNFSF6), not TNF itself. The term 
        may be overly broad.
      action: ACCEPT
      reason: While FAS does not directly respond to TNF, it is part of the 
        broader TNF receptor superfamily and uses similar death domain-mediated 
        signaling mechanisms. The IEA annotation based on logical inference is 
        acceptable as a general categorization of this signaling pathway family.
  - term:
      id: GO:0004888
      label: transmembrane signaling receptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS isoform 1 
        is a type I transmembrane receptor that binds FasL extracellularly and 
        transduces signals intracellularly via its death domain. This is a valid
        parent term of the more specific GO:0005031 (tumor necrosis factor 
        receptor activity).
      action: ACCEPT
      reason: 'Correct general molecular function for membrane-bound FAS. This IEA
        based on InterPro domain mapping is appropriate. Note: Does not apply to soluble
        isoforms 2-6 which lack the transmembrane domain.'
  - term:
      id: GO:0005516
      label: calmodulin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: FAS binds calmodulin in a region overlapping its death domain 
        (residues 230-254). This interaction has been structurally characterized
        by X-ray crystallography [PMID:24914971 cited in UniProt]. Calmodulin 
        binding may modulate FAS signaling.
      action: ACCEPT
      reason: UniProt documents interaction with CALM based on structural 
        evidence. IEA from keyword mapping is consistent with direct 
        experimental data. This represents a regulatory interaction that 
        modulates FAS function.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: ISOFORM-SPECIFIC annotation for SOLUBLE FAS isoforms (P25445-2 to
        P25445-6). UniProt explicitly states that isoforms 2-6 are secreted. 
        Soluble FAS lacking the transmembrane domain is released into the 
        extracellular space where it acts as a decoy receptor.
      action: ACCEPT
      reason: 'Correct localization for soluble FAS isoforms. IEA from UniProt subcellular
        location mapping is appropriate for the secreted isoforms. Note: Does not
        apply to membrane-bound isoform 1.'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS isoform 1 
        is a type I transmembrane protein localized to the plasma membrane where
        it functions as a death receptor. UniProt confirms cell membrane 
        localization for isoform 1.
      action: ACCEPT
      reason: 'Correct localization for membrane-bound FAS. IEA from UniProt subcellular
        location is appropriate. Note: Does not apply to soluble isoforms 2-6 which
        are secreted.'
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: CORE FUNCTION of membrane-bound FAS. Apoptosis is the primary 
        biological process mediated by FAS activation. Upon FasL binding, FAS 
        recruits FADD and caspase-8 to form the DISC, initiating the caspase 
        cascade leading to cell death.
      action: ACCEPT
      reason: 'This is the core biological process for FAS. IEA from combined automated
        methods is consistent with extensive experimental evidence. Note: Soluble
        isoforms have the opposite effect, blocking apoptosis.'
  - term:
      id: GO:0006955
      label: immune response
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: FAS plays a critical role in immune homeostasis through 
        elimination of autoreactive lymphocytes and termination of immune 
        responses via AICD. Defects in FAS cause ALPS, an autoimmune disorder. 
        The deep research confirms FAS-FasL is essential for peripheral 
        tolerance and immune regulation.
      action: ACCEPT
      reason: While overly broad, FAS does function in immune response contexts.
        The term encompasses FAS roles in lymphocyte homeostasis, peripheral 
        tolerance, and immune response termination. IEA from InterPro mapping is
        acceptable.
  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: FAS is a signaling receptor that transduces extracellular FasL 
        binding into intracellular signals. The signal transduction involves 
        death domain-mediated recruitment of FADD and caspase-8, leading to DISC
        formation and caspase activation.
      action: ACCEPT
      reason: Correct but very general term. FAS is indeed a signal transducing 
        receptor. More specific terms (e.g., Fas signaling pathway, extrinsic 
        apoptotic signaling) better capture its function.
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS isoform 1 
        is expressed on the cell surface where it can engage FasL on neighboring
        cells. Cell surface expression is essential for FAS-mediated apoptosis.
      action: ACCEPT
      reason: 'Correct localization for membrane-bound FAS. IEA from ARBA machine
        learning is consistent with experimental evidence. Note: Does not apply to
        soluble isoforms.'
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS isoform 1 
        is an integral membrane protein. This is a very general parent term of 
        plasma membrane.
      action: ACCEPT
      reason: Correct but overly general term. More specific terms (plasma 
        membrane, membrane raft) are more informative. IEA from InterPro mapping
        is appropriate.
  - term:
      id: GO:0031265
      label: CD95 death-inducing signaling complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). Duplicate of 
        IBA annotation for DISC localization. FAS is a core component of the 
        CD95 DISC along with FADD and caspase-8.
      action: ACCEPT
      reason: Correct localization. This IEA annotation is consistent with the 
        IBA annotation and extensive experimental evidence. Duplicates are 
        acceptable with different evidence codes.
  - term:
      id: GO:0042981
      label: regulation of apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: FAS regulates apoptosis - membrane-bound isoform 1 positively 
        regulates it by triggering cell death, while soluble isoforms 2-6 
        negatively regulate it by blocking FasL. This general term encompasses 
        both activities.
      action: ACCEPT
      reason: Correct but imprecise. The more specific child terms 
        (positive/negative regulation of apoptotic process) better capture the 
        isoform-specific functions. IEA is acceptable as a general 
        categorization.
  - term:
      id: GO:0045121
      label: membrane raft
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). Duplicate of 
        IBA annotation. FAS localizes to membrane rafts which facilitates DISC 
        assembly.
      action: ACCEPT
      reason: Correct localization. Consistent with IBA annotation and 
        experimental evidence. IEA from UniProt confirms this localization.
  - term:
      id: GO:0097191
      label: extrinsic apoptotic signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: CORE FUNCTION of membrane-bound FAS. FAS is the defining death 
        receptor of the extrinsic apoptotic signaling pathway. Upon FasL 
        binding, FAS recruits FADD via death domain interactions, forming the 
        DISC that activates caspase-8.
      action: ACCEPT
      reason: This is the core biological process for FAS. The extrinsic pathway
        is initiated by death receptors like FAS, in contrast to the intrinsic 
        (mitochondrial) pathway. IEA from ARBA is consistent with extensive 
        experimental evidence.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10918185
    review:
      summary: Generic protein binding term. FAS interacts with many proteins 
        including FADD, CASP8, RIPK1, DAXX, and others. This term is 
        uninformative and should be replaced with more specific molecular 
        function terms.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague and does 
        not provide useful information about FAS function. More specific terms 
        should be used.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
        - id: GO:0042802
          label: identical protein binding
      supported_by:
        - reference_id: PMID:10918185
          supporting_text: Negative regulation of Fas-mediated apoptosis by 
            FAP-1 in human cancer cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11003656
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague. More 
        specific molecular function terms should be used.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:11003656
          supporting_text: Inhibition of Daxx-mediated apoptosis by heat shock 
            protein 27.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11495919
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:11495919
          supporting_text: 2001 Aug 8. Apoptosis signal-regulating kinase 1 
            controls the proapoptotic function of death-associated protein 
            (Daxx) in the cytoplasm.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11606059
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:11606059
          supporting_text: Apoptosis-linked gene 2 binds to the death domain of 
            Fas and dissociates from Fas during Fas-mediated apoptosis in Jurkat
            cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11717445
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:11717445
          supporting_text: Caspase-10 is an initiator caspase in death receptor 
            signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12724420
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:12724420
          supporting_text: FAP-1 association with Fas (Apo-1) inhibits Fas 
            expression on the cell surface.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12887920
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:12887920
          supporting_text: Induction of TNF receptor I-mediated apoptosis via 
            two sequential signaling complexes.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16498403
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:16498403
          supporting_text: The role of receptor internalization in CD95 
            signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17047155
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:17047155
          supporting_text: 2006 Oct 17. Caspase-8 prevents sustained activation 
            of NF-kappaB in monocytes undergoing macrophagic differentiation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17159907
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:17159907
          supporting_text: Palmitoylation of CD95 facilitates formation of 
            SDS-stable receptor aggregates that initiate apoptosis signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18328427
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:18328427
          supporting_text: Yes and PI3K bind CD95 to signal invasion of 
            glioblastoma.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21382479
    review:
      summary: FAS-Caveolin-1 interaction study. Cav-1 regulates Fas signaling 
        and DISC formation. Generic protein binding term is uninformative.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:21382479
          supporting_text: the colocalization and interaction of Cav-1 and Fas 
            increased, followed by Fas multimer and DISC formation
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21625644
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:21625644
          supporting_text: 'Modulation of the CD95-induced apoptosis: the role of
            CD95 N-glycosylation.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21803845
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:21803845
          supporting_text: 2011 Jul 29. PMLRARα binds to Fas and suppresses 
            Fas-mediated apoptosis through recruiting c-FLIP in vivo.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25241761
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:25241761
          supporting_text: Oct 9. Using an in situ proximity ligation assay to 
            systematically profile endogenous protein-protein interactions in a 
            pathway network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35922511
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:35922511
          supporting_text: Aug 3. A physical wiring diagram for the human immune
            system.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7536190
    review:
      summary: FAS-FADD interaction. This study identified FADD as binding the 
        FAS death domain. More specific term needed.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:7536190
          supporting_text: A novel protein that specifically binds to the death 
            domain of Fas/APO1 but not to Fas/APO1 molecules with a loss of 
            function point mutation
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7538907
    review:
      summary: FAS-FADD interaction via death domains. More specific term 
        needed.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:7538907
          supporting_text: FADD, which binds Fas and Fas-FD5, a mutant of Fas 
            possessing enhanced killing activity, but not the functionally 
            inactive mutants Fas-LPR and Fas-FD8
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:21382479
    review:
      summary: FAS self-association/multimerization. FAS forms multimers upon 
        activation which is required for DISC assembly. This is a valid more 
        specific term than generic protein binding.
      action: ACCEPT
      reason: FAS self-association is well-documented and important for 
        signaling. The Fas-FADD death domain complex contains 5-7 FAS molecules,
        demonstrating FAS homo-oligomerization.
      supported_by:
        - reference_id: PMID:21382479
          supporting_text: the colocalization and interaction of Cav-1 and Fas 
            increased, followed by Fas multimer and DISC formation
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:7536190
    review:
      summary: FAS self-association. The death domain mediates FAS-FAS 
        interactions.
      action: ACCEPT
      reason: FAS self-association via death domains is well-established. 
        Required for DISC assembly.
      supported_by:
        - reference_id: PMID:7536190
          supporting_text: the region upstream to the death domain prompts 
            self-association of the protein
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:7538908
    review:
      summary: FAS self-association identified in yeast two-hybrid screen.
      action: ACCEPT
      reason: FAS-FAS interaction documented by RIP study. Consistent with DISC 
        architecture.
      supported_by:
        - reference_id: PMID:7538908
          supporting_text: 'we have identified two gene products that associate with
            the intracellular domain of Fas: Fas itself, and a novel 74 kDa protein
            we have named RIP'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). Direct 
        experimental evidence (HPA immunohistochemistry) for plasma membrane 
        localization.
      action: ACCEPT
      reason: 'Correct localization for membrane-bound FAS. IDA from HPA data is strong
        evidence. Note: Does not apply to soluble isoforms.'
  - term:
      id: GO:0005031
      label: tumor necrosis factor receptor activity
    evidence_type: IDA
    original_reference_id: PMID:12221075
    review:
      summary: CORE FUNCTION. Direct experimental demonstration of TNF receptor 
        activity. FAS binds FasL and activates downstream apoptotic signaling.
      action: ACCEPT
      reason: This is the core molecular function of FAS. IDA evidence from 
        direct assay confirms receptor activity. Consistent with IBA annotation.
      supported_by:
        - reference_id: PMID:12221075
          supporting_text: Through the induction of apoptosis, CD95 plays a 
            crucial role in the immune response and the elimination of cancer 
            cells
  - term:
      id: GO:0008625
      label: extrinsic apoptotic signaling pathway via death domain receptors
    evidence_type: IDA
    original_reference_id: PMID:12221075
    review:
      summary: CORE FUNCTION of membrane-bound FAS. FAS is the canonical death 
        domain receptor that initiates the extrinsic apoptotic pathway. This is 
        a highly specific and accurate term for FAS function.
      action: ACCEPT
      reason: This is the defining biological process for FAS. The term 
        precisely describes FAS-mediated apoptosis through death domain 
        interactions with FADD.
      supported_by:
        - reference_id: PMID:12221075
          supporting_text: Ligation of CD95 receptor activates a complex 
            signaling network that appears to implicate the generation of 
            reactive oxygen species (ROS)
  - term:
      id: GO:0036337
      label: Fas signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:12221075
    review:
      summary: CORE FUNCTION. The Fas signaling pathway is the specific pathway 
        initiated by FAS/CD95 ligation. This is the most precise process term 
        for FAS function.
      action: ACCEPT
      reason: This is the defining signaling pathway for FAS. Highly specific 
        and accurate.
      supported_by:
        - reference_id: PMID:12221075
          supporting_text: Ligation of CD95 receptor activates a complex 
            signaling network
  - term:
      id: GO:1903428
      label: positive regulation of reactive oxygen species biosynthetic process
    evidence_type: IDA
    original_reference_id: PMID:12221075
    review:
      summary: FAS activation triggers early ROS production. This study 
        demonstrated that anti-CD95 antibodies triggered early generation of ROS
        in T47D cells.
      action: KEEP_AS_NON_CORE
      reason: ROS production is a documented downstream effect of FAS signaling 
        but is not the core function. The primary function is apoptosis 
        induction.
      supported_by:
        - reference_id: PMID:12221075
          supporting_text: Anti-CD95 antibodies triggered an early generation of
            ROS in human breast cancer T47D cells
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15917238
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:15917238
          supporting_text: 2005 May 24. CD47 augments Fas/CD95-mediated 
            apoptosis.
  - term:
      id: GO:0008625
      label: extrinsic apoptotic signaling pathway via death domain receptors
    evidence_type: IDA
    original_reference_id: PMID:9333124
    review:
      summary: CORE FUNCTION. Duplicate annotation for extrinsic apoptotic 
        signaling via death domain receptors from different publication.
      action: ACCEPT
      reason: Core biological process for FAS. Consistent with other 
        annotations.
      supported_by:
        - reference_id: PMID:9333124
          supporting_text: Fas and Fas ligand interaction is necessary for human
            osteoblast apoptosis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18846110
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:18846110
          supporting_text: 2008 Oct 10. Identification of an antiapoptotic 
            protein complex at death receptors.
  - term:
      id: GO:0032872
      label: regulation of stress-activated MAPK cascade
    evidence_type: IMP
    original_reference_id: PMID:11096076
    review:
      summary: FAS ligation activates ASK1 and JNK/SAPK under glutamine 
        deprivation conditions. Duplicate of IBA annotation with experimental 
        evidence.
      action: KEEP_AS_NON_CORE
      reason: MAPK regulation is a secondary signaling output, not the core 
        function of FAS.
      supported_by:
        - reference_id: PMID:11096076
          supporting_text: Fas ligation activated apoptosis signal-regulating 
            kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK; also known as 
            stress-activated protein kinase (SAPK)) in Gln-deprived cells
  - term:
      id: GO:0034198
      label: cellular response to amino acid starvation
    evidence_type: IMP
    original_reference_id: PMID:11096076
    review:
      summary: FAS-mediated apoptosis is enhanced under glutamine starvation 
        conditions. This reflects context-dependent modulation of FAS signaling.
      action: KEEP_AS_NON_CORE
      reason: Amino acid starvation modulates FAS sensitivity but is not a core 
        function.
      supported_by:
        - reference_id: PMID:11096076
          supporting_text: HeLa cells were susceptible to Fas-mediated apoptosis
            under the condition of glutamine deprivation
  - term:
      id: GO:0036337
      label: Fas signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:11096076
    review:
      summary: CORE FUNCTION. Duplicate annotation for Fas signaling pathway 
        with IMP evidence.
      action: ACCEPT
      reason: Core signaling pathway for FAS. Consistent with IDA annotation.
      supported_by:
        - reference_id: PMID:11096076
          supporting_text: HeLa cells were susceptible to Fas-mediated apoptosis
  - term:
      id: GO:2001235
      label: positive regulation of apoptotic signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:11096076
    review:
      summary: CORE FUNCTION of membrane-bound FAS. FAS positively regulates 
        apoptotic signaling by initiating the caspase cascade.
      action: ACCEPT
      reason: 'Core function of membrane-bound FAS isoform 1. Note: Soluble isoforms
        have opposite effect.'
      supported_by:
        - reference_id: PMID:11096076
          supporting_text: HeLa cells were susceptible to Fas-mediated apoptosis
  - term:
      id: GO:0005516
      label: calmodulin binding
    evidence_type: IDA
    original_reference_id: PMID:24914971
    review:
      summary: FAS binds calmodulin in a region overlapping its death domain 
        (residues 230-254). Direct experimental evidence from structural 
        studies.
      action: ACCEPT
      reason: IDA evidence supports calmodulin binding. This may modulate FAS 
        signaling. Consistent with IEA annotation.
      supported_by:
        - reference_id: PMID:24914971
          supporting_text: Structural insights into the mechanism of calmodulin 
            binding to death receptors.
  - term:
      id: GO:0031264
      label: death-inducing signaling complex
    evidence_type: IDA
    original_reference_id: PMID:21803845
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). FAS is a core 
        component of the DISC. This is a more general term than GO:0031265 (CD95
        DISC).
      action: ACCEPT
      reason: Correct localization. DISC is the functional context for 
        FAS-mediated apoptosis.
      supported_by:
        - reference_id: PMID:21803845
          supporting_text: 2011 Jul 29. PMLRARα binds to Fas and suppresses 
            Fas-mediated apoptosis through recruiting c-FLIP in vivo.
  - term:
      id: GO:0097527
      label: necroptotic signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:16507998
    review:
      summary: FAS can trigger necroptosis via RIP1 when caspases are inhibited.
        IMP evidence from study showing RIP-dependent necrosis downstream of 
        death receptor ligation.
      action: KEEP_AS_NON_CORE
      reason: Necroptosis is a secondary pathway activated when apoptosis is 
        blocked. Consistent with IBA annotation.
      supported_by:
        - reference_id: PMID:16507998
          supporting_text: These observations demonstrate a novel mechanism 
            initiated through death receptor ligation and mediated by RIP that 
            results in the suppression of ANT activity and necrosis
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IMP
    original_reference_id: PMID:21625644
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). IMP evidence 
        for plasma membrane localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Consistent with IDA 
        and IEA annotations.
      supported_by:
        - reference_id: PMID:21625644
          supporting_text: 'Modulation of the CD95-induced apoptosis: the role of
            CD95 N-glycosylation.'
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IDA
    original_reference_id: PMID:21625644
    review:
      summary: 'CORE FUNCTION of membrane-bound FAS (isoform 1, P25445-1). FAS is
        the death receptor that initiates extrinsic apoptosis by forming the DISC
        (Death-Inducing Signaling Complex) with FADD and CASP8 upon FasL binding.
        Note: This function is OPPOSITE to soluble FAS isoforms (P25445-2 to P25445-6)
        which BLOCK apoptosis.'
      action: ACCEPT
      reason: Core pro-apoptotic function of canonical membrane-bound FAS. 
        Should ideally be isoform-specific to P25445-1 to distinguish from the 
        anti-apoptotic soluble isoforms.
      supported_by:
        - reference_id: PMID:21625644
          supporting_text: 'Modulation of the CD95-induced apoptosis: the role of
            CD95 N-glycosylation.'
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: IDA
    original_reference_id: PMID:22891283
    review:
      summary: ISOFORM-SPECIFIC (membrane-bound isoform 1 only). Direct 
        experimental evidence for cell surface localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Consistent with other
        annotations.
      supported_by:
        - reference_id: PMID:22891283
          supporting_text: 2012 Aug 13. Vesicles released by activated T cells 
            induce both Fas-mediated RIP-dependent apoptotic and Fas-independent
            nonapoptotic cell deaths.
  - term:
      id: GO:0097191
      label: extrinsic apoptotic signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:22891283
    review:
      summary: CORE FUNCTION. IMP evidence for extrinsic apoptotic signaling 
        pathway. Consistent with IEA annotation.
      action: ACCEPT
      reason: Core biological process for FAS.
      supported_by:
        - reference_id: PMID:22891283
          supporting_text: 2012 Aug 13. Vesicles released by activated T cells 
            induce both Fas-mediated RIP-dependent apoptotic and Fas-independent
            nonapoptotic cell deaths.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:20458337
    review:
      summary: FAS has been detected in extracellular exosomes. High-throughput 
        data analysis.
      action: KEEP_AS_NON_CORE
      reason: Exosomal localization may reflect secretion of soluble FAS 
        isoforms or membrane FAS in exosomes. Not a core localization.
      supported_by:
        - reference_id: PMID:20458337
          supporting_text: 2010 May 11. MHC class II-associated proteins in 
            B-cell exosomes and potential functional implications for exosome 
            biogenesis.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-139952
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Consistent with other
        annotations.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-141310
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Duplicate from 
        different pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3465429
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Duplicate from 
        different pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3465448
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Duplicate from 
        different pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3465459
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Duplicate from 
        different pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5675456
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Duplicate from 
        different pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6800001
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Duplicate from 
        different pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-71050
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Duplicate from 
        different pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-73945
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Duplicate from 
        different pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-75244
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Duplicate from 
        different pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-83586
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Duplicate from 
        different pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-83650
    review:
      summary: ISOFORM-SPECIFIC. TAS from Reactome for plasma membrane 
        localization.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. Duplicate from 
        different pathway.
  - term:
      id: GO:0071455
      label: cellular response to hyperoxia
    evidence_type: IMP
    original_reference_id: PMID:21382479
    review:
      summary: FAS-mediated apoptosis is induced by hyperoxia. Study showed 
        Cav-1 regulates Fas signaling in hyperoxia-induced apoptosis.
      action: KEEP_AS_NON_CORE
      reason: Hyperoxia response is a specific context where FAS is activated. 
        Not a core function.
      supported_by:
        - reference_id: PMID:21382479
          supporting_text: We found that Cav-1 regulated Fas signaling and 
            mediated the communication between extrinsic and intrinsic pathways
  - term:
      id: GO:0031265
      label: CD95 death-inducing signaling complex
    evidence_type: IDA
    original_reference_id: PMID:20935634
    review:
      summary: ISOFORM-SPECIFIC. Direct structural evidence for FAS in the CD95 
        DISC. This study solved the Fas-FADD death domain complex structure 
        showing 5-7 Fas DD and 5 FADD DD.
      action: ACCEPT
      reason: Core localization for membrane-bound FAS. Strong structural 
        evidence.
      supported_by:
        - reference_id: PMID:20935634
          supporting_text: The death-inducing signaling complex (DISC) formed by
            the death receptor Fas, the adaptor protein FADD and caspase-8 
            mediates the extrinsic apoptotic program
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IMP
    original_reference_id: PMID:20935634
    review:
      summary: CORE FUNCTION of membrane-bound FAS. IMP evidence from 
        structure-function studies showing that ALPS mutations disrupt FAS-FADD 
        interaction and apoptosis.
      action: ACCEPT
      reason: Core pro-apoptotic function. Consistent with other annotations.
      supported_by:
        - reference_id: PMID:20935634
          supporting_text: Mutations in Fas that disrupt the DISC cause 
            autoimmune lymphoproliferative syndrome (ALPS)
  - term:
      id: GO:0045121
      label: membrane raft
    evidence_type: IDA
    original_reference_id: PMID:21382479
    review:
      summary: ISOFORM-SPECIFIC. Direct experimental evidence for FAS 
        localization in membrane rafts. Cav-1 interaction facilitates FAS 
        clustering in rafts.
      action: ACCEPT
      reason: Correct localization for membrane-bound FAS. IDA evidence is 
        strong.
      supported_by:
        - reference_id: PMID:21382479
          supporting_text: the colocalization and interaction of Cav-1 and Fas 
            increased, followed by Fas multimer and DISC formation
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21109225
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:21109225
          supporting_text: Epub 2010 Nov 25. Whole-exome-sequencing-based 
            discovery of human FADD deficiency.
  - term:
      id: GO:0071260
      label: cellular response to mechanical stimulus
    evidence_type: IEP
    original_reference_id: PMID:19593445
    review:
      summary: FAS expression is modulated by mechanical stimulus. IEP 
        (expression pattern) evidence suggests FAS is involved in cellular 
        response to mechanical stress.
      action: KEEP_AS_NON_CORE
      reason: Mechanical stimulus response is a specific context. IEP evidence 
        is weaker than direct functional evidence.
      supported_by:
        - reference_id: PMID:19593445
          supporting_text: Expression of the Bcl-2 protein BAD promotes prostate
            cancer growth.
  - term:
      id: GO:0031264
      label: death-inducing signaling complex
    evidence_type: IDA
    original_reference_id: PMID:11101870
    review:
      summary: ISOFORM-SPECIFIC. Direct experimental evidence for FAS in the 
        DISC. Consistent with other DISC annotations.
      action: ACCEPT
      reason: Core localization for membrane-bound FAS.
      supported_by:
        - reference_id: PMID:11101870
          supporting_text: Fas triggers an alternative, caspase-8-independent 
            cell death pathway using the kinase RIP as effector molecule.
  - term:
      id: GO:0019900
      label: kinase binding
    evidence_type: IPI
    original_reference_id: PMID:7538908
    review:
      summary: FAS binds RIP1 (RIPK1), a serine/threonine kinase. RIP contains a
        kinase domain and interacts with FAS death domain.
      action: ACCEPT
      reason: Valid molecular function annotation. RIP1 kinase binding is 
        well-documented.
      supported_by:
        - reference_id: PMID:7538908
          supporting_text: RIP contains an N-terminal region with homology to 
            protein kinases and a C-terminal region containing a cytoplasmic 
            motif (death domain)
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IDA
    original_reference_id: PMID:9681877
    review:
      summary: CORE FUNCTION. Direct experimental evidence for FAS-mediated 
        apoptosis.
      action: ACCEPT
      reason: Core biological process for membrane-bound FAS. Consistent with 
        other annotations.
      supported_by:
        - reference_id: PMID:9681877
          supporting_text: Effect of age and apoptosis on the mouse homologue of
            the huWRN gene.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15465831
    review:
      summary: Generic protein binding term. Uninformative about FAS function.
      action: MODIFY
      reason: Per curation guidelines, 'protein binding' is too vague.
      proposed_replacement_terms:
        - id: GO:0005031
          label: tumor necrosis factor receptor activity
      supported_by:
        - reference_id: PMID:15465831
          supporting_text: 2004 Oct 1. A death receptor-associated 
            anti-apoptotic protein, BRE, inhibits mitochondrial apoptotic 
            pathway.
  - term:
      id: GO:0042981
      label: regulation of apoptotic process
    evidence_type: NAS
    original_reference_id: PMID:7533181
    review:
      summary: FAS regulates apoptosis - membrane-bound form triggers it, 
        soluble forms block it. NAS evidence from review article.
      action: ACCEPT
      reason: Correct general term. Consistent with IEA annotation.
      supported_by:
        - reference_id: PMID:7533181
          supporting_text: Three functional soluble forms of the human 
            apoptosis-inducing Fas molecule are produced by alternative 
            splicing.
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: TAS
    original_reference_id: PMID:10871852
    review:
      summary: CORE FUNCTION. TAS evidence for apoptotic process involvement.
      action: ACCEPT
      reason: Core biological process for FAS. Consistent with other 
        annotations.
      supported_by:
        - reference_id: PMID:10871852
          supporting_text: p38 protects human melanoma cells from UV-induced 
            apoptosis through down-regulation of NF-kappaB activity and Fas 
            expression.
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: TAS
    original_reference_id: PMID:1375228
    review:
      summary: CORE FUNCTION. Original characterization of APO-1/Fas showing 
        apoptosis induction.
      action: ACCEPT
      reason: Core biological process. Seminal paper identifying APO-1/Fas as 
        apoptosis inducer.
      supported_by:
        - reference_id: PMID:1375228
          supporting_text: Cross-linking of the APO-1 antigen by anti-APO-1 
            induced programmed cell death, apoptosis, of APO-1 positive cells
  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: TAS
    original_reference_id: PMID:9360929
    review:
      summary: FAS is a signaling receptor. TAS evidence for signal 
        transduction.
      action: ACCEPT
      reason: Correct but general term. Consistent with IEA annotation.
      supported_by:
        - reference_id: PMID:9360929
          supporting_text: Requirement for the CD95 receptor-ligand pathway in 
            c-Myc-induced apoptosis.
  - term:
      id: GO:0038023
      label: signaling receptor activity
    evidence_type: TAS
    original_reference_id: PMID:1375228
    review:
      summary: CORE FUNCTION. FAS is a cell surface signaling receptor.
      action: ACCEPT
      reason: Correct molecular function. Consistent with other annotations.
      supported_by:
        - reference_id: PMID:1375228
          supporting_text: The APO-1 antigen as defined by the mouse monoclonal 
            antibody anti-APO-1 was previously found to be expressed on the cell
            surface
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: TAS
    original_reference_id: PMID:7510905
    review:
      summary: ISOFORM-SPECIFIC ANNOTATION. This annotation refers to SOLUBLE 
        FAS isoforms (P25445-2 to P25445-6), NOT the canonical membrane-bound 
        form. PMID:7510905 explicitly demonstrates that "a human Fas messenger 
        RNA variant capable of encoding a soluble Fas molecule lacking the 
        transmembrane domain" produces a protein where "Supernatants from cells 
        transfected with the variant messenger RNA blocked apoptosis induced by 
        the antibody to Fas."
      action: ACCEPT
      reason: Correct annotation for soluble FAS isoforms. This is the 
        antagonistic function of the TMdel isoforms that act as decoy receptors.
        Should ideally be annotated to specific isoforms P25445-2/6, not the 
        canonical membrane-bound P25445-1.
      supported_by:
        - reference_id: PMID:7510905
          supporting_text: Supernatants from cells transfected with the variant 
            messenger RNA blocked apoptosis induced by the antibody to Fas
  - term:
      id: GO:0065003
      label: protein-containing complex assembly
    evidence_type: TAS
    original_reference_id: PMID:10875918
    review:
      summary: FAS forms preassociated complexes before ligand binding. This 
        study showed that FAS preassociation in the PRELIGAND assembly domain is
        required for signaling.
      action: ACCEPT
      reason: Valid biological process. FAS preassociation and DISC assembly are
        well-documented.
      supported_by:
        - reference_id: PMID:10875918
          supporting_text: Preassociated Fas complexes were found in living 
            cells by means of fluorescence resonance energy transfer between 
            variants of green fluorescent protein
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: NAS
    original_reference_id: PMID:7533181
    review:
      summary: Cytosolic localization may refer to the intracellular death 
        domain portion of membrane-bound FAS or to cleaved/soluble forms. NAS 
        evidence is weak.
      action: UNDECIDED
      reason: Unclear what cytosolic localization refers to. FAS is primarily a 
        membrane protein. May refer to cleaved forms or ICD. NAS evidence 
        insufficient for confident assessment.
      supported_by:
        - reference_id: PMID:7533181
          supporting_text: Three functional soluble forms of the human 
            apoptosis-inducing Fas molecule are produced by alternative 
            splicing.
  - term:
      id: GO:0038023
      label: signaling receptor activity
    evidence_type: NAS
    original_reference_id: PMID:7533181
    review:
      summary: CORE FUNCTION. FAS is a signaling receptor. NAS evidence from 
        review article.
      action: ACCEPT
      reason: Correct molecular function. Consistent with TAS annotation.
      supported_by:
        - reference_id: PMID:7533181
          supporting_text: Three functional soluble forms of the human 
            apoptosis-inducing Fas molecule are produced by alternative 
            splicing.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on on
      inter-ontology links
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10871852
    title: p38 protects human melanoma cells from UV-induced apoptosis through 
      down-regulation of NF-kappaB activity and Fas expression.
    findings: []
  - id: PMID:10875918
    title: Fas preassociation required for apoptosis signaling and dominant 
      inhibition by pathogenic mutations.
    findings: []
  - id: PMID:10918185
    title: Negative regulation of Fas-mediated apoptosis by FAP-1 in human 
      cancer cells.
    findings: []
  - id: PMID:11003656
    title: Inhibition of Daxx-mediated apoptosis by heat shock protein 27.
    findings: []
  - id: PMID:11096076
    title: Glutamine-dependent antiapoptotic interaction of human 
      glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1.
    findings: []
  - id: PMID:11101870
    title: Fas triggers an alternative, caspase-8-independent cell death pathway
      using the kinase RIP as effector molecule.
    findings: []
  - id: PMID:11495919
    title: Apoptosis signal-regulating kinase 1 controls the proapoptotic 
      function of death-associated protein (Daxx) in the cytoplasm.
    findings: []
  - id: PMID:11606059
    title: Apoptosis-linked gene 2 binds to the death domain of Fas and 
      dissociates from Fas during Fas-mediated apoptosis in Jurkat cells.
    findings: []
  - id: PMID:11717445
    title: Caspase-10 is an initiator caspase in death receptor signaling.
    findings: []
  - id: PMID:12221075
    title: Glutathione peroxidase-1 protects from CD95-induced apoptosis.
    findings: []
  - id: PMID:12724420
    title: FAP-1 association with Fas (Apo-1) inhibits Fas expression on the 
      cell surface.
    findings: []
  - id: PMID:12887920
    title: Induction of TNF receptor I-mediated apoptosis via two sequential 
      signaling complexes.
    findings: []
  - id: PMID:1375228
    title: Purification and molecular cloning of the APO-1 cell surface antigen,
      a member of the tumor necrosis factor/nerve growth factor receptor 
      superfamily. Sequence identity with the Fas antigen.
    findings: []
  - id: PMID:15465831
    title: A death receptor-associated anti-apoptotic protein, BRE, inhibits 
      mitochondrial apoptotic pathway.
    findings: []
  - id: PMID:15917238
    title: CD47 augments Fas/CD95-mediated apoptosis.
    findings: []
  - id: PMID:16498403
    title: The role of receptor internalization in CD95 signaling.
    findings: []
  - id: PMID:16507998
    title: Inhibition of ADP/ATP exchange in receptor-interacting 
      protein-mediated necrosis.
    findings: []
  - id: PMID:17047155
    title: Caspase-8 prevents sustained activation of NF-kappaB in monocytes 
      undergoing macrophagic differentiation.
    findings: []
  - id: PMID:17159907
    title: Palmitoylation of CD95 facilitates formation of SDS-stable receptor 
      aggregates that initiate apoptosis signaling.
    findings: []
  - id: PMID:18328427
    title: Yes and PI3K bind CD95 to signal invasion of glioblastoma.
    findings: []
  - id: PMID:18846110
    title: Identification of an antiapoptotic protein complex at death 
      receptors.
    findings: []
  - id: PMID:19593445
    title: Expression of the Bcl-2 protein BAD promotes prostate cancer growth.
    findings: []
  - id: PMID:20458337
    title: MHC class II-associated proteins in B-cell exosomes and potential 
      functional implications for exosome biogenesis.
    findings: []
  - id: PMID:20935634
    title: The Fas-FADD death domain complex structure reveals the basis of DISC
      assembly and disease mutations.
    findings: []
  - id: PMID:21109225
    title: Whole-exome-sequencing-based discovery of human FADD deficiency.
    findings: []
  - id: PMID:21382479
    title: Caveolin-1 mediates Fas-BID signaling in hyperoxia-induced apoptosis.
    findings: []
  - id: PMID:21625644
    title: 'Modulation of the CD95-induced apoptosis: the role of CD95 N-glycosylation.'
    findings: []
  - id: PMID:21803845
    title: PMLRARα binds to Fas and suppresses Fas-mediated apoptosis through 
      recruiting c-FLIP in vivo.
    findings: []
  - id: PMID:22891283
    title: Vesicles released by activated T cells induce both Fas-mediated 
      RIP-dependent apoptotic and Fas-independent nonapoptotic cell deaths.
    findings: []
  - id: PMID:24914971
    title: Structural insights into the mechanism of calmodulin binding to death
      receptors.
    findings: []
  - id: PMID:25241761
    title: Using an in situ proximity ligation assay to systematically profile 
      endogenous protein-protein interactions in a pathway network.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:35922511
    title: A physical wiring diagram for the human immune system.
    findings: []
  - id: PMID:7510905
    title: Protection from Fas-mediated apoptosis by a soluble form of the Fas 
      molecule.
    findings: []
  - id: PMID:7533181
    title: Three functional soluble forms of the human apoptosis-inducing Fas 
      molecule are produced by alternative splicing.
    findings: []
  - id: PMID:7536190
    title: A novel protein that interacts with the death domain of Fas/APO1 
      contains a sequence motif related to the death domain.
    findings: []
  - id: PMID:7538907
    title: FADD, a novel death domain-containing protein, interacts with the 
      death domain of Fas and initiates apoptosis.
    findings: []
  - id: PMID:7538908
    title: 'RIP: a novel protein containing a death domain that interacts with Fas/APO-1
      (CD95) in yeast and causes cell death.'
    findings: []
  - id: PMID:9333124
    title: Fas and Fas ligand interaction is necessary for human osteoblast 
      apoptosis.
    findings: []
  - id: PMID:9360929
    title: Requirement for the CD95 receptor-ligand pathway in c-Myc-induced 
      apoptosis.
    findings: []
  - id: PMID:9681877
    title: Effect of age and apoptosis on the mouse homologue of the huWRN gene.
    findings: []
  - id: Reactome:R-HSA-139952
    title: Caspase-8 processing in the DISC
    findings: []
  - id: Reactome:R-HSA-141310
    title: FASL:FAS Receptor Trimer:FADD complex binds procaspase-10
    findings: []
  - id: Reactome:R-HSA-3465429
    title: FLIP(S) and procaspase-8 form heterodimer
    findings: []
  - id: Reactome:R-HSA-3465448
    title: Caspase-8 and FLIP(L) processing at DISC
    findings: []
  - id: Reactome:R-HSA-3465459
    title: FLIP(L) and procaspase-8 form heterodimer in FasL/CD95 signaling
    findings: []
  - id: Reactome:R-HSA-5675456
    title: FLIP(L) and procaspase-8 form heterodimer
    findings: []
  - id: Reactome:R-HSA-6800001
    title: TP53 family members stimulate FAS gene expression
    findings: []
  - id: Reactome:R-HSA-71050
    title: Trimerization of the FASL:FAS receptor complex
    findings: []
  - id: Reactome:R-HSA-73945
    title: FAS-mediated dimerization of procaspase-8
    findings: []
  - id: Reactome:R-HSA-75244
    title: FASL binds FAS Receptor
    findings: []
  - id: Reactome:R-HSA-83586
    title: FASL:FAS Receptor Trimer:FADD complex binds pro-Caspase-8
    findings: []
  - id: Reactome:R-HSA-83650
    title: FasL:Fas binds FADD
    findings: []
  - id: file:human/FAS/FAS-deep-research-perplexity.md
    title: Deep research report on FAS
    findings: []
core_functions:
  - molecular_function:
      id: GO:0005031
      label: tumor necrosis factor receptor activity
    description: FAS (CD95/APO-1) is a type I transmembrane death receptor of 
      the TNF receptor superfamily (TNFRSF6). The extracellular domain contains 
      three cysteine-rich domains (CRDs) that bind FasL (FASLG/CD95L). This is 
      the defining molecular function of FAS. ISOFORM-SPECIFIC to membrane-bound
      isoform 1 (P25445-1).
    directly_involved_in:
      - id: GO:0008625
        label: extrinsic apoptotic signaling pathway via death domain receptors
      - id: GO:0036337
        label: Fas signaling pathway
    locations:
      - id: GO:0009897
        label: external side of plasma membrane
      - id: GO:0045121
        label: membrane raft
    in_complex:
      id: GO:0031265
      label: CD95 death-inducing signaling complex
alternative_products:
  - name: '1'
    id: P25445-1
    description: >-
      The canonical membrane-bound pro-apoptotic isoform (335 AA). Contains the transmembrane
      domain and intracellular death domain. Triggers apoptosis upon FasL binding
      by recruiting
      FADD and caspase-8 to form the death-inducing signaling complex (DISC). Most
      GO annotations
      for FAS refer to this isoform.
  - name: 2 (del2, D)
    id: P25445-2
    sequence_note: VSP_006481, VSP_006482
    description: >-
      A soluble isoform lacking the transmembrane domain. Acts as a decoy receptor
      that binds
      FasL and BLOCKS apoptosis by preventing membrane Fas activation. Functionally
      ANTAGONISTIC
      to isoform 1.
  - name: 3 (del3, E)
    id: P25445-3
    sequence_note: VSP_006483, VSP_006484
    description: >-
      A soluble isoform lacking the transmembrane domain. Acts as a decoy receptor
      that inhibits
      Fas-mediated apoptosis. Functionally antagonistic to isoform 1.
  - name: 4 (B)
    id: P25445-4
    sequence_note: VSP_006485, VSP_006486
    description: >-
      A soluble isoform lacking the transmembrane domain. Acts as a decoy receptor
      that inhibits
      Fas-mediated apoptosis. Functionally antagonistic to isoform 1.
  - name: 5 (C)
    id: P25445-5
    sequence_note: VSP_006487, VSP_006488
    description: >-
      A soluble isoform lacking the transmembrane domain. Acts as a decoy receptor
      that inhibits
      Fas-mediated apoptosis. Functionally antagonistic to isoform 1.
  - name: 6 (TMdel, A)
    id: P25445-6
    sequence_note: VSP_006489
    description: >-
      A soluble isoform specifically noted for deletion of the transmembrane domain
      (TMdel).
      Acts as a decoy receptor that inhibits Fas-mediated apoptosis by sequestering
      FasL.
      Elevated in autoimmune diseases where it may contribute to impaired apoptosis
      of
      autoreactive lymphocytes.
  - name: 7 (FasExo8Del)
    id: P25445-7
    sequence_note: VSP_045235, VSP_045236
    description: >-
      An isoform with deletion of exon 8 sequences. Less well characterized than the
      membrane
      and soluble isoforms. Functional role not well established.

FAS

Gene Description