TNFRSF1A

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005031 tumor necrosis factor receptor activity	IBA GO_REF:0000033	ACCEPT	Summary: TNFR1 is the defining member of the TNF receptor superfamily and its primary molecular function is TNF receptor activity. This is the most precise and appropriate MF term for this receptor (PMID:2158863, PMID:12887920). Reason: TNF receptor activity is the core molecular function of TNFRSF1A. The receptor binds both soluble and membrane-bound TNF trimers via its extracellular cysteine-rich domains and transduces signal through its intracellular death domain. IBA annotation is well supported by phylogenetic analysis across vertebrate orthologs and extensive experimental evidence. Supporting Evidence: PMID:12887920 TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. PMID:7758105 Many diverse activities of tumor necrosis factor (TNF) are signaled through TNF receptor 1 (TNFR1). We have identified a novel 34 kDa protein, designated TRADD, that specifically interacts with an intracellular domain of TNFR1 known to be essential for mediating programmed cell death.
GO:0006954 inflammatory response	IBA GO_REF:0000033	ACCEPT	Summary: TNFR1 is a principal mediator of TNF-driven inflammatory responses. Via Complex I signaling (TRADD/RIPK1/TRAF2/cIAP1-2/LUBAC), it activates NF-kappaB and MAPKs to induce pro-inflammatory gene expression, including cytokines, chemokines, and adhesion molecules (PMID:12887920, PMID:8565075). Reason: Inflammatory response is a core biological process for TNFR1. As the primary receptor for soluble TNF, it is the major conduit for TNF-mediated inflammation. The IBA annotation is phylogenetically sound and well supported by extensive literature. Supporting Evidence: PMID:12887920 The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. PMID:8565075 Tumor necrosis factor (TNF) can induce apoptosis and activate NF-kappa B through signaling cascades emanating from TNF receptor 1 (TNFR1).
GO:0045121 membrane raft	IBA GO_REF:0000033	ACCEPT	Summary: TNFR1 has been shown to localize to membrane rafts/lipid rafts where it assembles signaling complexes. IBA annotation is consistent with direct experimental evidence (IDA from PMID:17010968). Reason: TNFR1 localization to membrane rafts is supported by both phylogenetic inference and direct experimental evidence. Lipid raft partitioning is relevant to TNFR1 signaling platform assembly and signal transduction. Supporting Evidence: PMID:17010968 metalloproteinase inhibition increases the proportion of ADAM17 substrates (TNF and its receptors TNFR1 and TNFR2) in lipid rafts
GO:0043120 tumor necrosis factor binding	IBA GO_REF:0000033	ACCEPT	Summary: TNF binding is a core molecular function of TNFR1. The receptor binds trimeric TNF-alpha (and LTA) via its extracellular cysteine-rich domains CRD2 and CRD3. Crystal structure of the TNF-beta-TNFR1 complex (PDB:1TNR) confirms the binding interface (PMID:8387891). Reason: TNF binding is the primary ligand-recognition function of TNFR1 and is well supported by structural, biochemical, and phylogenetic evidence. The IBA annotation is appropriate and at the correct level of specificity. Supporting Evidence: PMID:9435233 Calculation of the dissociation constant (Kd) from the association and dissociation rate constants determined at 37 degrees C revealed a remarkable high affinity for TNF binding to the 60-kDa TNF type 1 receptor (TNF-R1; Kd = 1.9 x 10(-11) M)
GO:0043235 receptor complex	IBA GO_REF:0000033	ACCEPT	Summary: TNFR1 forms homotrimeric receptor complexes via the PLAD domain even in the absence of ligand, and upon TNF binding assembles larger signaling complexes. IBA annotation is consistent with IDA evidence (PMID:23382219). Reason: The receptor complex annotation reflects the well-established biology of TNFR1 homotrimerization and is phylogenetically conserved. More specific CC term GO:0002947 (TNFRSF complex) is also annotated separately. Supporting Evidence: PMID:23382219 We further show that the PX-FERM proteins share a promiscuous ability to bind a wide array of putative cargo molecules, including receptor tyrosine kinases, and propose a model for their coordinated molecular interactions with membrane, cargo, and regulatory proteins
GO:0000139 Golgi membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation based on UniProt subcellular location mapping. TNFR1 transits through the Golgi during biosynthesis and is detected at the Golgi membrane. Consistent with IDA evidence (PMID:22801493). Reason: Golgi membrane localization is supported by direct experimental evidence (IDA from Gregory et al. 2012) and reflects the transit of TNFR1 through the secretory pathway. The IEA annotation is correct and consistent with higher-quality evidence. Supporting Evidence: PMID:22801493 While FL-TNFR1 localizes to the Golgi apparatus, Δ6-TNFR1 demonstrated a more diffuse intracellular distribution (Fig. 2), consistent with the absence of the Golgi-retention motif.
GO:0005031 tumor necrosis factor receptor activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for TNF receptor activity, consistent with IBA and TAS annotations for the same term. Reason: Redundant with IBA annotation but correct. IEA evidence from multiple automated methods converges on this core function.
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation based on UniProt subcellular location. TNFR1 ectodomain is shed by ADAM17/TACE producing soluble TNFR1 (sTNFR1/TBPI) found in the extracellular region. Consistent with multiple TAS and NAS annotations. Reason: The soluble form of TNFR1 is well documented in the extracellular region. This IEA annotation is broader than some of the experimental evidence but not incorrect.
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for plasma membrane localization, consistent with extensive TAS and IPI evidence. Reason: TNFR1 is a type I transmembrane protein whose primary localization is the plasma membrane. This is well supported by numerous other annotations.
GO:0006693 prostaglandin metabolic process	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: IEA annotation from InterPro domain IPR020419 (TNFR_1A). While TNF signaling via TNFR1 can indirectly influence prostaglandin metabolism through NF-kappaB-mediated induction of COX-2, TNFR1 does not directly participate in prostaglandin metabolism. This is a downstream pleiotropic effect of TNF signaling. Reason: The link between TNFR1 and prostaglandin metabolism is indirect and downstream. TNF/TNFR1 signaling can activate NF-kappaB, which induces COX-2 expression, leading to prostaglandin production. However, annotating TNFR1 directly to prostaglandin metabolic process overstates its involvement. TNFR1 does not catalyze or directly regulate prostaglandin synthesis. MADD (which binds TNFR1) was shown to activate ERK and phospholipase A2, providing a link to arachidonic acid release, but this is still indirect (PMID:9115275). Supporting Evidence: PMID:9115275 These data indicate that MADD links TNFR1 with MAP kinase activation and arachidonic acid release and provide further insight into the mechanisms by which TNF exerts its pleiotropic effects.
GO:0006915 apoptotic process	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for apoptotic process. TNFR1 is indeed a key death receptor that signals apoptosis via Complex II (TRADD/FADD/caspase-8). However, the more specific term GO:0008625 (extrinsic apoptotic signaling pathway via death domain receptors) is already annotated. Reason: While the more specific death-domain-mediated extrinsic apoptosis term is also annotated, this broader IEA annotation is not wrong. TNFR1 is a classical death receptor and apoptosis induction is a core function. It is acceptable for IEA to be broader than more specific experimental annotations.
GO:0006954 inflammatory response	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro domain, consistent with IBA and ISS annotations for the same term. Reason: Redundant with IBA but correct. Inflammatory response is a core process for TNFR1.
GO:0007165 signal transduction	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro death domain (IPR000488). Signal transduction is indeed a function of TNFR1 but this is very generic. More specific terms like TNF-mediated signaling pathway are also annotated. Reason: While very broad, signal transduction is not incorrect for a signaling receptor. More specific terms are annotated elsewhere. It is acceptable for IEA annotations to use broader terms.
GO:0010468 regulation of gene expression	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: IEA annotation from ARBA machine learning. TNFR1 signaling through NF-kappaB does regulate gene expression, but this is a very general downstream consequence of TNFR1 signaling rather than a direct function. Reason: Regulation of gene expression is an extremely broad term. While TNFR1 does activate NF-kappaB which is a transcription factor, annotating the receptor itself to "regulation of gene expression" is too distant from the receptor's direct molecular role. The annotation chain is receptor -> adaptors -> kinase cascades -> IKK -> NF-kappaB -> gene expression. More specific annotations (positive regulation of NF-kappaB signaling, positive regulation of transcription by RNA pol II) are already present.
GO:0010557 positive regulation of macromolecule biosynthetic process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: IEA annotation from ARBA machine learning. Very generic biological process that is an indirect downstream consequence of TNFR1 signaling. Reason: This is an extremely broad term. While TNFR1 signaling via NF-kappaB can promote transcription and thus macromolecule biosynthesis, this annotation provides no useful specificity about TNFR1 function. More specific terms are already annotated.
GO:0033209 tumor necrosis factor-mediated signaling pathway	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation consistent with IMP and TAS annotations for the same core signaling pathway. Reason: TNF-mediated signaling pathway is a core process for TNFR1 and is the most specific pathway term. Consistent with multiple higher-evidence annotations.
GO:0050793 regulation of developmental process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: IEA annotation from ARBA machine learning. Very broad developmental process term. Reason: While TNFR1 has roles in developmental apoptosis (valve development, morphogenesis), those are annotated with more specific terms. This very broad IEA term does not add useful information and is likely derived from indirect pathway annotations.
GO:0051239 regulation of multicellular organismal process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: IEA annotation from ARBA machine learning. Extremely broad term. Reason: This is one of the broadest possible BP annotations. While technically not wrong, it provides no useful information about TNFR1 function. More specific process terms are already annotated.
GO:0005515 protein binding	IPI PMID:11684708 Keratin attenuates tumor necrosis factor-induced cytotoxicit...	MODIFY	Summary: IPI evidence for interaction with TRADD (Q15628). TRADD is the primary adaptor recruited to the TNFR1 death domain and is central to both NF-kappaB and apoptosis signaling (PMID:7758105, PMID:8565075). Reason: Protein binding is uninformative. The interaction with TRADD via death domains is the defining signaling mechanism of TNFR1. This should be annotated with a more specific MF term such as GO:0005031 (tumor necrosis factor receptor activity) which encompasses the adaptor recruitment function, or ideally a death domain binding term. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:7758105 We have identified a novel 34 kDa protein, designated TRADD, that specifically interacts with an intracellular domain of TNFR1 known to be essential for mediating programmed cell death. PMID:11684708 We have now identified human TNF receptor type 1 (TNFR1)-associated death domain protein (TRADD) to be the K18-interacting protein.
GO:0005515 protein binding	IPI PMID:12887920 Induction of TNF receptor I-mediated apoptosis via two seque...	MODIFY	Summary: IPI evidence for interaction with TNF (P01375). TNF binding is the primary ligand-receptor interaction for TNFR1 (PMID:12887920). Reason: The interaction with TNF is already captured by the more specific GO:0043120 (tumor necrosis factor binding). Protein binding is uninformative for this well-characterized receptor-ligand interaction. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:12887920 TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2
GO:0005515 protein binding	IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp...	MODIFY	Summary: IPI evidence for interactions with TNF (P01375), ubiquitin (P0CG47), and MON2 (Q7Z3U7) from a large-scale TNF-alpha/NF-kappaB pathway mapping study. Reason: Protein binding is uninformative. The TNF interaction is captured by GO:0043120. The ubiquitin interaction likely reflects TNFR1 complex ubiquitination (RIPK1 ubiquitination in Complex I). Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:14743216 the mapping of a protein interaction network around 32 known and candidate TNF-alpha/NF-kappa B pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies using RNA interference
GO:0005515 protein binding	IPI PMID:16611992 Competitive control of independent programs of tumor necrosi...	MODIFY	Summary: IPI evidence for interactions with RIPK1 (Q13546) and TRADD (Q15628). These are core signaling adaptors in the TNFR1 Complex I. Reason: Protein binding is uninformative. RIPK1 and TRADD recruitment to the TNFR1 death domain is the defining mechanism of TNFR1 signaling. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:16611992 TRADD and RIP1 compete for recruitment to the TNFR1 signaling complex and the distinct programs of cell death.
GO:0005515 protein binding	IPI PMID:18022363 IAP antagonists target cIAP1 to induce TNFalpha-dependent ap...	MODIFY	Summary: IPI evidence for interaction with RIPK1 (Q13546). Reason: Protein binding is uninformative. RIPK1 interaction via the death domain is integral to TNFR1 signaling. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:18022363 Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha
GO:0005515 protein binding	IPI PMID:19524513 Phosphorylation-driven assembly of the RIP1-RIP3 complex reg...	MODIFY	Summary: IPI evidence for interactions with RIPK1 (Q13546) and TRADD (Q15628). Reason: Protein binding is uninformative for these well-characterized death domain-mediated interactions. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:19524513 The kinase RIP1 is crucial for programmed necrosis, but also mediates activation of the prosurvival transcription factor NF-kappaB.
GO:0005515 protein binding	IPI PMID:19641494 Riboflavin kinase couples TNF receptor 1 to NADPH oxidase.	MODIFY	Summary: IPI evidence for interactions with TRADD (Q15628) and RFK (Q969G6). The RFK interaction is noteworthy as RFK (riboflavin kinase) has been reported to bind TNFR1 and may play a role in TNF-induced superoxide production. Reason: Protein binding is uninformative. The TRADD interaction is part of core signaling. The RFK interaction is interesting but protein binding does not capture the functional significance. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:19641494 Here we identify riboflavin kinase (RFK, formerly known as flavokinase) as a previously unrecognized TNF-receptor-1 (TNFR1)-binding protein that physically and functionally couples TNFR1 to NADPH oxidase.
GO:0005515 protein binding	IPI PMID:19781631 Proteinase-activated receptor-2 mediated inhibition of TNFal...	MODIFY	Summary: IPI evidence for interactions with RIPK1 (Q13546) and TRADD (Q15628) in context of PAR2-mediated inhibition of TNF-stimulated JNK. Reason: Protein binding is uninformative for core TNFR1 adaptor interactions. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:19781631 Activation of PAR(2) was found to disrupt TNFR1 binding to RIP and TRADD and this was reversed by both GF109203X and YM25480.
GO:0005515 protein binding	IPI PMID:20080539 The Polycomb group protein EED couples TNF receptor 1 to neu...	MODIFY	Summary: IPI evidence for interaction with TNF (P01375). Reason: TNF binding is captured by GO:0043120. Protein binding is uninformative. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:20080539 EED and nSMase2 are recruited to the TNF-R1.FAN.RACK1-complex in a timeframe concurrent with activation of nSMase2.
GO:0005515 protein binding	IPI PMID:20103630 Multivalent DR5 peptides activate the TRAIL death pathway an...	MODIFY	Summary: IPI evidence for interaction with TNF (P01375) from a study on DR5 peptides. Reason: Protein binding is uninformative. TNF binding is captured by GO:0043120. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:20103630 Ongoing clinical trials are exploring anticancer approaches based on signaling by TRAIL, a ligand for the cell death receptors DR4 and DR5.
GO:0005515 protein binding	IPI PMID:22028622 Smac mimetic bypasses apoptosis resistance in FADD- or caspa...	MODIFY	Summary: IPI evidence for interaction with TNF (P01375). Reason: Protein binding is uninformative. TNF binding captured by GO:0043120. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:22028622 Smac mimetic primes apoptosis-resistant, FADD- or caspase-8-deficient leukemia cells for TNFα-induced necroptosis in a synergistic manner.
GO:0005515 protein binding	IPI PMID:22817896 The RIP1/RIP3 necrosome forms a functional amyloid signaling...	MODIFY	Summary: IPI evidence for interaction with RIPK1 (Q13546). Reason: Protein binding is uninformative for this core signaling interaction. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:22817896 RIP1 and RIP3 kinases are central players in TNF-induced programmed necrosis.
GO:0005515 protein binding	IPI PMID:23955153 Pathogen blocks host death receptor signalling by arginine G...	MODIFY	Summary: IPI evidence for interactions with TNF (P01375) and TRADD (Q15628). This paper (Li et al. 2013, Nature) demonstrated that bacterial NleB1 GlcNAcylates Arg-376 in the TNFR1 death domain, blocking death domain interactions. Reason: Protein binding is uninformative. TNF/TRADD interactions are captured by more specific terms. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:23955153 NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase activity that specifically modified a conserved arginine in these death domains
GO:0005515 protein binding	IPI PMID:24070898 Progranulin directly binds to the CRD2 and CRD3 of TNFR extr...	MODIFY	Summary: IPI evidence for interactions with TNF (P01375) and progranulin/GRN (P28799). Progranulin was reported to bind CRD2 and CRD3 of TNFR1, competing with TNF. Reason: Protein binding is uninformative. The TNF interaction is captured by GO:0043120. The progranulin interaction is interesting but protein binding does not capture the specificity. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:24070898 Protein interaction assays with mutants of the TNFR extracellular domain demonstrated that CRD2 and CRD3 of TNFR are important for the interaction with PGRN, similar to the binding to TNFα.
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	MODIFY	Summary: IPI evidence for interaction with TNF (P01375) from an in situ proximity ligation assay study. Reason: Protein binding is uninformative. TNF binding captured by GO:0043120. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:25241761 we collected ∼ 700 primary antibodies and employed a highly sensitive and specific technique, an in situ proximity ligation assay, to investigate 1204 endogenous PPIs in HeLa cells, and 557 PPIs of them tested positive
GO:0005515 protein binding	IPI PMID:25911380 The seventh zinc finger motif of A20 is required for the sup...	MODIFY	Summary: IPI evidence for interaction with TNF (P01375). Reason: Protein binding is uninformative. TNF binding captured by GO:0043120. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:25911380 The ubiquitin-editing enzyme A20 suppresses nuclear factor-κB (NF-κB) activation and tumor necrosis factor-α (TNF-α)-induced apoptosis in a deubiquitinating and ubiquitin ligase activity-dependent manner.
GO:0005515 protein binding	IPI PMID:2848815 Human tumor necrosis factor-alpha receptor. Purification by ...	MODIFY	Summary: IPI evidence for interaction with TNF (P01375). This is one of the earliest papers on TNFR1, demonstrating purification of the receptor by immunoaffinity chromatography based on TNF binding. Reason: Protein binding is uninformative. The TNF binding is captured by GO:0043120. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:2848815 The receptor for human tumor necrosis factor-alpha (TNF-alpha) was isolated from a subclone of the human histiocytic lymphoma cell line U937. These cells exhibit a single class of high affinity receptors (Kd = 0.51 +/- 0.25 nM)
GO:0005515 protein binding	IPI PMID:32822567 A Human IgSF Cell-Surface Interactome Reveals a Complex Netw...	MODIFY	Summary: IPI evidence for interaction with TNF (P01375) from a large-scale IgSF interactome study. Reason: Protein binding is uninformative. TNF binding captured by GO:0043120. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:32822567 We executed an interactome screen of 564 human cell-surface and secreted proteins, most of which are immunoglobulin superfamily (IgSF) proteins, using a high-throughput, automated ELISA-based screening platform
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: IPI evidence for interactions with TNF (P01375), ubiquitin (P0CG47), RIPK1 (Q13546), and TRADD (Q15628) from a dual proteome-scale network study. Reason: Protein binding is uninformative for these well-characterized interactions. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. The first, BioPlex 3.0, results from affinity purification of 10,128 human proteins-half the proteome-in 293T cells and includes 118,162 interactions among 14,586 proteins.
GO:0005515 protein binding	IPI PMID:35922511 A physical wiring diagram for the human immune system.	MODIFY	Summary: IPI evidence for interaction with TNF (P01375) from a physical wiring diagram of the human immune system. Reason: Protein binding is uninformative. TNF binding captured by GO:0043120. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:35922511 we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes
GO:0005515 protein binding	IPI PMID:36179048 Novel biochemical, structural, and systems insights into inf...	MODIFY	Summary: IPI evidence for interaction with TNF (P01375). Reason: Protein binding is uninformative. TNF binding captured by GO:0043120. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:36179048 we set out to map the TNF-RSC composition with high quantitative accuracy and confidence
GO:0005515 protein binding	IPI PMID:7758105 The TNF receptor 1-associated protein TRADD signals cell dea...	MODIFY	Summary: IPI evidence for interaction with TRADD (Q15628). This is the landmark paper by Hsu et al. (1995) identifying TRADD as the primary TNFR1 adaptor that signals cell death and NF-kappaB activation. Reason: Protein binding is uninformative for this critical signaling interaction. TRADD binding to the TNFR1 death domain is the initiating step in all TNFR1 signaling cascades. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:7758105 We have identified a novel 34 kDa protein, designated TRADD, that specifically interacts with an intracellular domain of TNFR1 known to be essential for mediating programmed cell death. Overexpression of TRADD leads to two major TNF-induced responses, apoptosis and activation of NF-kappa B.
GO:0005515 protein binding	IPI PMID:8565075 TRADD-TRAF2 and TRADD-FADD interactions define two distinct ...	MODIFY	Summary: IPI evidence for interaction with TRADD (Q15628). Hsu et al. (1996) showed that TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNFR1 signaling pathways. Reason: Protein binding is uninformative. The TRADD interaction is part of core receptor signaling. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:8565075 TRADD directly interacts with TRAF2 and FADD, signal transducers that activate NF-kappa B and induce apoptosis, respectively.
GO:0005515 protein binding	IPI PMID:8621670 Systematic mutational analysis of the death domain of the tu...	MODIFY	Summary: IPI evidence for interaction with TRADD (Q15628) from mutational analysis of the TRADD death domain. Reason: Protein binding is uninformative for the core TNFR1-TRADD death domain interaction. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:8621670 A TNF-R1-associated protein TRADD has been discovered that interacts with the death domain of the receptor. Elevated expression of TRADD in cells triggers both NF-kappaB activation and programmed cell death pathways.
GO:0005515 protein binding	IPI PMID:8943045 The tumor necrosis factor receptor 2 signal transducers TRAF...	MODIFY	Summary: IPI evidence for interaction with TRADD (Q15628). Reason: Protein binding is uninformative for the core TNFR1-TRADD interaction. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:8943045 The recruitment of TRAF2 and c-IAP1 to TNF-R1 is TNF-dependent, is mediated by TRADD, and is independent of TNF-R2.
GO:0042802 identical protein binding	IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp...	ACCEPT	Summary: IPI evidence for TNFR1 self-interaction (P19438 with P19438). TNFR1 homotrimerizes through the PLAD domain in CRD1, which is essential for receptor preassembly and signaling competence. Reason: TNFR1 homotrimerization via the PLAD domain is a well-established feature of TNFR1 biology. Self-association is required for proper receptor function and is biologically meaningful, making identical protein binding an appropriate annotation in this case. Supporting Evidence: PMID:14743216 the mapping of a protein interaction network around 32 known and candidate TNF-alpha/NF-kappa B pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies using RNA interference
GO:0042802 identical protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	ACCEPT	Summary: IPI evidence for TNFR1 self-interaction from a large-scale liver interactome study. Reason: Consistent with the known PLAD-mediated homotrimerization of TNFR1. Supporting Evidence: PMID:21988832 we map the interactions of an unbiased selection of 5026 human liver expression proteins by yeast two-hybrid technology and establish a human liver protein interaction network (HLPN) composed of 3484 interactions among 2582 proteins
GO:0042802 identical protein binding	IPI PMID:7758105 The TNF receptor 1-associated protein TRADD signals cell dea...	ACCEPT	Summary: IPI evidence for TNFR1 self-interaction from the landmark TRADD paper (Hsu et al. 1995). Reason: TNFR1 homotrimerization is well-established and required for signaling. Supporting Evidence: PMID:7758105 Many diverse activities of tumor necrosis factor (TNF) are signaled through TNF receptor 1 (TNFR1). We have identified a novel 34 kDa protein, designated TRADD, that specifically interacts with an intracellular domain of TNFR1 known to be essential for mediating programmed cell death.
GO:0003176 aortic valve development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation transferred from mouse Tnfrsf1a (P25118) via Ensembl Compara. Mouse knockout studies show TNFR1 role in cardiac valve development. Reason: Aortic valve development is a specific developmental phenotype observed in mouse knockouts. While plausible based on ortholog evidence, this is a pleiotropic downstream effect of TNFR1 signaling in a specific tissue context, not a core function. ISS annotation for the same term is also present.
GO:0003177 pulmonary valve development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation transferred from mouse Tnfrsf1a (P25118) via Ensembl Compara. Reason: Similar to aortic valve development, this is a pleiotropic developmental phenotype from mouse knockout studies, not a core function of TNFR1.
GO:0003332 negative regulation of extracellular matrix constituent secretion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation transferred from mouse Tnfrsf1a. TNF/TNFR1 signaling can modulate ECM turnover, but this is a downstream tissue-specific effect. Reason: This is a downstream consequence of TNF/TNFR1 signaling in specific tissue contexts (e.g., cardiac fibrosis). Not a core function.
GO:0009986 cell surface	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for cell surface localization. TNFR1 is a type I transmembrane protein present at the cell surface. Reason: Cell surface localization is correct and consistent with TNFR1 being a transmembrane receptor that binds extracellular TNF.
GO:0010467 gene expression	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA annotation transferred from mouse. Very broad term. Reason: Gene expression is extremely broad. TNFR1 signaling activates NF-kappaB which induces gene expression, but this is too distant from the receptor's direct function. More specific terms (positive regulation of transcription by RNA polymerase II) already capture this.
GO:0010614 negative regulation of cardiac muscle hypertrophy	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation transferred from mouse. TNFR1 has been implicated in cardiac remodeling through mouse knockout studies. Reason: This is a tissue-specific physiological role of TNFR1 in cardiac biology, a downstream pleiotropic effect rather than a core function.
GO:0038023 signaling receptor activity	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation transferred from mouse. Signaling receptor activity is correct but less specific than GO:0005031 (TNF receptor activity). Reason: While less specific than TNF receptor activity, signaling receptor activity is correct for TNFR1 and it is acceptable for IEA annotations to be at a broader level of specificity.
GO:0043123 positive regulation of canonical NF-kappaB signal transduction	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation transferred from mouse. TNFR1 Complex I signaling activates canonical NF-kappaB through IKK complex recruitment and IkappaB phosphorylation (PMID:12887920). Reason: Positive regulation of canonical NF-kappaB signaling is a core output of TNFR1 Complex I. This is well supported by extensive literature and is one of the primary signaling outcomes of TNF/TNFR1 engagement. Supporting Evidence: PMID:12887920 The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B.
GO:0045121 membrane raft	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation transferred from mouse, consistent with IBA and IDA annotations. Reason: Redundant with IBA and IDA but correct. Membrane raft localization is experimentally verified for TNFR1.
GO:0048143 astrocyte activation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation transferred from mouse. TNF/TNFR1 signaling can activate astrocytes in the CNS, but this is a cell-type-specific downstream effect. Reason: Astrocyte activation is a specific physiological response in the CNS context. While TNFR1 does play roles in neuroinflammation, this is a cell-type-specific pleiotropic effect rather than a core function.
GO:0060856 establishment of blood-brain barrier	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation transferred from mouse. TNFR1 has been implicated in blood-brain barrier regulation through mouse studies. Reason: Blood-brain barrier establishment is a tissue-specific developmental/physiological role for TNFR1 in the CNS. Not a core function of the receptor.
GO:0071222 cellular response to lipopolysaccharide	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA annotation transferred from mouse. LPS signaling via TLR4 induces TNF production, which then signals through TNFR1. This is a secondary response where TNFR1 responds to autocrine/paracrine TNF produced in response to LPS, not a direct response to LPS. Reason: TNFR1 does not directly respond to LPS. Rather, LPS signals through TLR4 to induce TNF production, and the secreted TNF then activates TNFR1. Annotating TNFR1 to "cellular response to lipopolysaccharide" conflates the TNF response with the LPS response. The receptor responds to TNF, not LPS.
GO:1900119 positive regulation of execution phase of apoptosis	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation transferred from mouse. TNFR1 can trigger apoptosis via Complex II (TRADD/FADD/caspase-8), leading to execution phase apoptosis. Reason: TNFR1 is a classical death receptor and positive regulation of the execution phase of apoptosis is a direct consequence of Complex II signaling. This is a core function. Supporting Evidence: PMID:12887920 In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II).
GO:1902339 positive regulation of apoptotic process involved in morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation transferred from mouse. TNFR1-mediated apoptosis plays roles in developmental morphogenesis, particularly in cardiac valve formation. Reason: Developmental apoptosis during morphogenesis is a tissue-specific function. While plausible based on mouse data, this is not a core function of TNFR1.
GO:0005886 plasma membrane	IPI PMID:8387891 Crystal structure of the soluble human 55 kd TNF receptor-hu...	ACCEPT	Summary: IPI evidence from the crystal structure of the TNFR1-TNF-beta complex (Banner et al. 1993), which characterized the extracellular domain of the membrane-bound receptor. Reason: Plasma membrane localization is fundamental for TNFR1 as a type I transmembrane receptor. Supporting Evidence: PMID:8387891 The structure of the complex defines the orientation of the ligand with respect to the cell membrane and provides a model for TNF receptor activation.
GO:0007250 activation of NF-kappaB-inducing kinase activity	NAS PMID:33824270 Membrane lymphotoxin-α(2)β is a novel tumor necrosis factor ...	UNDECIDED	Summary: NAS annotation for activation of NF-kappaB-inducing kinase (NIK) activity. TNFR1 Complex I signals primarily through the canonical NF-kappaB pathway (IKK-dependent). NIK activation is more typically associated with the non-canonical NF-kappaB pathway, which is primarily triggered by TNFR2, CD40, BAFFR, and LTbetaR rather than TNFR1. Reason: NIK is primarily associated with the non-canonical NF-kappaB pathway, which is not the principal pathway activated by TNFR1. While there may be some context-dependent activation, this annotation may be inaccurate for TNFR1. The referenced publication (PMID:33824270) focuses on LTα2β as a novel TNFR2 agonist and its interaction with TNFR1, but does not specifically demonstrate NIK activation through TNFR1. The canonical pathway via IKK complex is the primary NF-kappaB activation mechanism for TNFR1. Supporting Evidence: PMID:33824270 LTα2β interacts not only with TNFR1 but also with TNFR2.
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	IMP PMID:21410936 Signal pathways in astrocytes activated by cross-talk betwee...	KEEP AS NON CORE	Summary: IMP evidence for TNFR1 involvement in JAK-STAT signaling. TNF has been reported to activate STAT signaling in some contexts, though this is not the primary signaling pathway. Reason: JAK-STAT signaling is not a primary output of TNFR1. The core signaling pathways are NF-kappaB (Complex I) and apoptosis/necroptosis (Complex II/necrosome). JAK-STAT activation by TNFR1 may occur in specific cellular contexts but is not a core function. The IMP evidence from PMID:21410936 supports this as a real but non-core function. Supporting Evidence: PMID:21410936 signaling pathways for Jak1/2 were inhibited by anti-TNFR1 antibody.
GO:0033209 tumor necrosis factor-mediated signaling pathway	IMP PMID:21410936 Signal pathways in astrocytes activated by cross-talk betwee...	ACCEPT	Summary: IMP evidence for TNF-mediated signaling pathway. This is the most specific and appropriate pathway term for TNFR1. Reason: TNF-mediated signaling pathway is the primary pathway for TNFR1 and this IMP annotation appropriately captures this core function. Supporting Evidence: PMID:21410936 EAE score, expression of TNFR1, and co-localization of TNFR1 and astrocytes were enhanced in brain of the EAE model.
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:21410936 Signal pathways in astrocytes activated by cross-talk betwee...	KEEP AS NON CORE	Summary: IMP evidence that TNFR1 signaling leads to positive regulation of transcription by RNA polymerase II, presumably through NF-kappaB activation. Reason: TNFR1 signaling activates NF-kappaB, which in turn drives transcription. This is a downstream consequence of the core signaling pathway. While real, it is several steps removed from the receptor's direct function. Supporting Evidence: PMID:21410936 the secreted cytokines re-activate astrocytes via Jak/STAT1701 pathways, and then release more cytokines that contribute to exacerbating the development of EAE.
GO:0033209 tumor necrosis factor-mediated signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse Tnfrsf1a (MGI:1314884). Core pathway for TNFR1. Reason: Consistent with IMP and TAS annotations for the same term. Core pathway.
GO:0038023 signaling receptor activity	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse ortholog. Correct but less specific than GO:0005031. Reason: Signaling receptor activity is correct for TNFR1. Less specific than TNF receptor activity but not wrong.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3371353	ACCEPT	Summary: TAS from Reactome reaction "Soluble TNF-alpha binds TNFR1". Plasma membrane is correct. Reason: Correct localization. Part of Reactome TNF signaling pathway annotation.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5357757	ACCEPT	Summary: TAS from Reactome "BIRC(cIAP1/2) ubiquitinates RIPK1". Plasma membrane is correct. Reason: Correct localization for Complex I signaling events.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5357776	ACCEPT	Summary: TAS from Reactome "TNFR1 complex recruits IKK". Plasma membrane is correct. Reason: Correct localization for Complex I signaling events.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5357780	ACCEPT	Summary: TAS from Reactome "TNFR1 complex recruits BIRC2/3". Plasma membrane is correct. Reason: Correct localization for Complex I signaling events.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5357845	ACCEPT	Summary: TAS from Reactome "K63polyUb-RIPK1 is deubiquitinated". Plasma membrane is correct. Reason: Correct localization for TNFR1 complex regulation.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5357860	ACCEPT	Summary: TAS from Reactome "TNFR1 complex recruits TAK1 complex". Plasma membrane is correct. Reason: Correct localization for Complex I signaling events.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5357904	ACCEPT	Summary: TAS from Reactome "TNFR1 complex binds LUBAC". Plasma membrane is correct. Reason: Correct localization for Complex I signaling events.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5357928	ACCEPT	Summary: TAS from Reactome "CLIP3 and CYLD bind TNF signaling complex". Plasma membrane correct. Reason: Correct localization for TNFR1 complex regulation.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5626953	ACCEPT	Summary: TAS from Reactome "TNF-alpha:TNFR1 binds DENN/MADD". Plasma membrane is correct. Reason: Correct localization for ceramide production pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5626981	ACCEPT	Summary: TAS from Reactome for neutral sphingomyelinase pathway. Plasma membrane is correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5626982	ACCEPT	Summary: TAS from Reactome for NSMAF-RACK1 binding. Plasma membrane is correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5626988	ACCEPT	Summary: TAS from Reactome for NSMAF binding. Plasma membrane is correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5634221	ACCEPT	Summary: TAS from Reactome "TRAF1 binds TRAF2 within TNFR1 signaling complex". Plasma membrane correct. Reason: Correct localization for Complex I.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5669097	ACCEPT	Summary: TAS from Reactome "LTA trimer binds TNFRSF1A,1B,14". Plasma membrane is correct. Reason: Correct localization for LTA binding to TNFR1 at the plasma membrane.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5693055	ACCEPT	Summary: TAS from Reactome "TAX1BP1:A20 binds RIPK1 complexes". Plasma membrane correct. Reason: Correct localization for TNFR1 complex regulation.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5693108	ACCEPT	Summary: TAS from Reactome "A20 ubiquitinates RIPK1". Plasma membrane is correct. Reason: Correct localization for TNFR1 complex regulation.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-83582	ACCEPT	Summary: TAS from Reactome "TRADD:TRAF2:RIP1 dissociates from TNFR1". Plasma membrane correct. Reason: Correct localization for Complex I to Complex II transition.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-83656	ACCEPT	Summary: TAS from Reactome "TNF:TNFR1 binds TRADD, TRAF2 and RIPK1". Plasma membrane correct. Reason: Correct localization for Complex I assembly.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-83660	ACCEPT	Summary: TAS from Reactome "Membrane-anchored TNF-alpha binds TNFR1". Plasma membrane correct. Reason: Correct localization for membrane-TNF binding.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9793679	ACCEPT	Summary: TAS from Reactome "LUBAC ubiquitinates RIPK1 at K627". Plasma membrane correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9793680	ACCEPT	Summary: TAS from Reactome "OPTN binds polyUb-RIPK1 within TNFR1 complex". Plasma membrane correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9796342	ACCEPT	Summary: TAS from Reactome "MIB2 binds RIPK1 within TNFR1 complex". Plasma membrane correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9796346	ACCEPT	Summary: TAS from Reactome "MIB2 ubiquitinates RIPK1". Plasma membrane correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9796379	ACCEPT	Summary: TAS from Reactome "CYLD:SPATA2:LUBAC binds TNFR1 complex". Plasma membrane correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9817362	ACCEPT	Summary: TAS from Reactome for LUBAC-mediated RIPK1 ubiquitination. Plasma membrane correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9817397	ACCEPT	Summary: TAS from Reactome "TBK1/IKBKE phosphorylate RIPK1 at T189". Plasma membrane correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9817400	ACCEPT	Summary: TAS from Reactome "CYLD hydrolyses K63polyUb on RIPK1". Plasma membrane correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9817411	ACCEPT	Summary: TAS from Reactome "TBK1/IKBKE binds Met1-polyUb in TNFR1 complex". Plasma membrane correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9818789	ACCEPT	Summary: TAS from Reactome "CHUK/IKBKB phosphorylate RIPK1 at S25". Plasma membrane correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9818975	ACCEPT	Summary: TAS from Reactome "CYLD hydrolyses M1polyUb on RIPK1". Plasma membrane correct. Reason: Correct localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9824874	ACCEPT	Summary: TAS from Reactome "OPTN recruits CYLD to TNFR1 complex". Plasma membrane correct. Reason: Correct localization.
GO:0005515 protein binding	IPI PMID:8985253 RAIDD is a new 'death' adaptor molecule.	MODIFY	Summary: IPI evidence for interaction with CRMA/p78560 (BAG4/SODD). BAG4 (Silencer of Death Domains) binds to the TNFR1 death domain and prevents spontaneous signaling in the absence of ligand (PMID:9915703). Reason: Protein binding is uninformative. BAG4/SODD interaction with the TNFR1 death domain is a specific regulatory mechanism that keeps the receptor silenced until ligand binding. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:9915703 TNF treatment released SODD from TNF-R1, permitting the recruitment of proteins such as TRADD and TRAF2 to the active TNF-R1 signaling complex.
GO:0002947 tumor necrosis factor receptor superfamily complex	TAS PMID:24966471 Tumor necrosis factor alpha - a link between neuroinflammati...	ACCEPT	Summary: TAS annotation placing TNFR1 as part of the TNF receptor superfamily complex. Reason: This is the most specific CC term for TNFR1. It accurately reflects that TNFR1 forms homotrimeric complexes and assembles multi-protein signaling complexes. Supporting Evidence: PMID:24966471 Tumor necrosis factor alpha (TNF- α) is a proinflammatory cytokine that exerts both homeostatic and pathophysiological roles in the central nervous system.
GO:0016020 membrane	TAS PMID:24966471 Tumor necrosis factor alpha - a link between neuroinflammati...	ACCEPT	Summary: TAS annotation for membrane localization. Very general term. Reason: While very general, membrane localization is correct for this transmembrane protein. More specific terms (plasma membrane, Golgi membrane) are also annotated. Supporting Evidence: PMID:24966471 Tumor necrosis factor alpha (TNF- α) is a proinflammatory cytokine that exerts both homeostatic and pathophysiological roles in the central nervous system.
GO:0033209 tumor necrosis factor-mediated signaling pathway	TAS PMID:24966471 Tumor necrosis factor alpha - a link between neuroinflammati...	ACCEPT	Summary: TAS annotation for TNF-mediated signaling pathway from ARUK-UCL curation. Reason: Core pathway annotation for TNFR1. Consistent with IMP and ISS annotations. Supporting Evidence: PMID:24966471 TNF-α can potentiate glutamate-mediated cytotoxicity by two complementary mechanisms: indirectly, by inhibiting glutamate transport on astrocytes, and directly, by rapidly triggering the surface expression of Ca(+2) permeable-AMPA receptors and NMDA receptors, while decreasing inhibitory GABAA receptors on neurons.
GO:0043120 tumor necrosis factor binding	IPI PMID:9435233 The type 1 receptor (CD120a) is the high-affinity receptor f...	ACCEPT	Summary: IPI evidence for TNF binding from ARUK-UCL curation, with evidence of binding to TNF (P01375). Reason: TNF binding is a core molecular function of TNFR1. Well supported by structural and biochemical data. Supporting Evidence: PMID:9435233 Calculation of the dissociation constant (Kd) from the association and dissociation rate constants determined at 37 degrees C revealed a remarkable high affinity for TNF binding to the 60-kDa TNF type 1 receptor (TNF-R1; Kd = 1.9 x 10(-11) M)
GO:0005515 protein binding	IPI PMID:24130170 SH3RF2 functions as an oncogene by mediating PAK4 protein st...	MODIFY	Summary: IPI evidence for interactions with RIPK1 (Q13546), TRADD (Q15628), and SH3RF2 (Q8TEC5). Kim et al. (2014) showed SH3RF2 facilitates RIPK1 and TRADD recruitment to TNFR1. Reason: Protein binding is uninformative. The interactions describe core TNFR1 signaling complex assembly. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:24130170 ablation of SH3RF2 expression attenuates TRADD (TNFR-associated death domain) recruitment to tumor necrosis factor-α (TNF-α) receptor 1 and hinders downstream signals
GO:0003176 aortic valve development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse Tnfrsf1a (P25118) by BHF-UCL curators. Reason: Developmental process from mouse knockout data. Not a core function of TNFR1. Duplicate of IEA annotation.
GO:0003177 pulmonary valve development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse. Duplicate of IEA annotation. Reason: Developmental process from mouse knockout data. Not a core function.
GO:0003332 negative regulation of extracellular matrix constituent secretion	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse. Duplicate of IEA annotation. Reason: Tissue-specific downstream effect. Not a core function.
GO:1902339 positive regulation of apoptotic process involved in morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse. Duplicate of IEA annotation. Reason: Developmental apoptosis. Not a core function, but a real pleiotropic role.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6785047	ACCEPT	Summary: TAS from Reactome IL-10 signaling pathway. The soluble TNFR1 ectodomain is found in the extracellular region. Reason: The soluble form of TNFR1 (sTNFR1) is present in the extracellular region and is relevant to IL-10 signaling regulation of inflammatory mediators.
GO:0033209 tumor necrosis factor-mediated signaling pathway	IMP PMID:25816133 Tumor necrosis factor disrupts claudin-5 endothelial tight j...	ACCEPT	Summary: IMP evidence for TNF-mediated signaling pathway from PMID:25816133. Reason: Core pathway annotation supported by mutant phenotype evidence. Supporting Evidence: PMID:25816133 TNF disrupts tight junction-dependent HDMEC barriers in discrete steps
GO:0072659 protein localization to plasma membrane	IMP PMID:25816133 Tumor necrosis factor disrupts claudin-5 endothelial tight j...	KEEP AS NON CORE	Summary: IMP evidence that TNFR1 is involved in protein localization to the plasma membrane. This likely reflects TNFR1 trafficking or its role in recruiting other proteins to the plasma membrane via signaling complex assembly. Reason: While TNFR1 does assemble signaling complexes at the plasma membrane, "protein localization to plasma membrane" is not a core function. It may reflect a secondary observation in the experiment. Supporting Evidence: PMID:25816133 All these responses require NF-κB signaling, shown by inhibition with Bay 11 or overexpression of IκB super-repressor
GO:1903140 regulation of establishment of endothelial barrier	IMP PMID:25816133 Tumor necrosis factor disrupts claudin-5 endothelial tight j...	KEEP AS NON CORE	Summary: IMP evidence for TNFR1 role in endothelial barrier regulation. TNF/TNFR1 signaling is known to increase endothelial permeability, relevant to inflammation. Reason: Endothelial barrier regulation is a physiologically important but tissue-specific downstream effect of TNF/TNFR1 signaling. Not a core function of the receptor. Supporting Evidence: PMID:25816133 Capillary leak in severe sepsis involves disruption of endothelial cell tight junctions.
GO:0005515 protein binding	IPI PMID:24440909 A novel role for the apoptosis inhibitor ARC in suppressing ...	MODIFY	Summary: IPI evidence for interaction with Q9D1X0 (a mouse protein). Cross-species interaction data. Reason: Protein binding is uninformative. Cross-species interaction evidence. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:24440909 The mechanism underlying these effects is an interaction of ARC with TNF receptor 1 that interferes with recruitment of RIP1, a critical mediator of TNFα-induced regulated necrosis.
GO:0043235 receptor complex	IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm...	ACCEPT	Summary: IDA evidence for TNFR1 as part of a receptor complex, from structural biology study on PX-FERM protein interactions with transmembrane cargo. Reason: TNFR1 forms homotrimeric receptor complexes and is part of larger signaling complexes. Direct experimental evidence supports this annotation. Supporting Evidence: PMID:23382219 the PX-FERM proteins share a promiscuous ability to bind a wide array of putative cargo molecules, including receptor tyrosine kinases, and propose a model for their coordinated molecular interactions with membrane, cargo, and regulatory proteins
GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors	TAS PMID:8612133 TNF-dependent recruitment of the protein kinase RIP to the T...	ACCEPT	Summary: TAS annotation for the extrinsic apoptotic signaling pathway via death domain receptors. TNFR1 is a classical death domain receptor that triggers extrinsic apoptosis through Complex II (TRADD/FADD/caspase-8) (PMID:12887920, PMID:8565075). Reason: This is one of the most precise and appropriate BP annotations for TNFR1. The extrinsic apoptotic pathway via death domain receptors is a core function of TNFR1, well supported by the landmark studies on TRADD, FADD, and caspase-8 recruitment. Supporting Evidence: PMID:12887920 In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). PMID:8565075 A FADD mutant lacking its N-terminal 79 amino acids is a dominant-negative inhibitor of TNF-induced apoptosis, but does not inhibit NF-kappa B activation.
GO:0000139 Golgi membrane	IDA PMID:22801493 TNF receptor 1 genetic risk mirrors outcome of anti-TNF ther...	ACCEPT	Summary: IDA evidence for Golgi membrane localization from Gregory et al. (2012, Nature). This study on the MS-associated TNFRSF1A variant showed TNFR1 in the Golgi. Reason: Direct experimental evidence for Golgi localization. TNFR1 transits through the Golgi during biosynthesis. Some disease-associated variants cause ER/Golgi retention. Supporting Evidence: PMID:22801493 While FL-TNFR1 localizes to the Golgi apparatus, Δ6-TNFR1 demonstrated a more diffuse intracellular distribution
GO:0005515 protein binding	IPI PMID:10848577 Stat1 as a component of tumor necrosis factor alpha receptor...	MODIFY	Summary: IPI evidence for interaction with STAT1 (P42224). Bhattacharyya et al. showed Stat1 as a component of the TNFR1-TRADD signaling complex. Reason: Protein binding is uninformative. The STAT1 interaction is part of TNFR1 signaling complex assembly. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:10848577 Stat1 is involved in the TNFR1-TRADD signaling complex, as determined by employing a novel antibody array screening method.
GO:0005615 extracellular space	IDA PMID:13130484 Heterogeneity among patients with tumor necrosis factor rece...	ACCEPT	Summary: IDA evidence for extracellular space localization. The soluble form of TNFR1 (sTNFR1) is found in the extracellular space after ADAM17/TACE-mediated ectodomain shedding. Reason: sTNFR1 is well documented in extracellular fluids (serum, urine) and acts as a decoy receptor. This is a physiologically important localization. Supporting Evidence: PMID:13130484 Plasma sTNFRSF1A levels were low in TRAPS patients in whom renal amyloidosis had not developed
GO:0050728 negative regulation of inflammatory response	IMP PMID:13130484 Heterogeneity among patients with tumor necrosis factor rece...	KEEP AS NON CORE	Summary: IMP evidence for negative regulation of inflammatory response. This likely reflects the anti-inflammatory role of soluble TNFR1 (sTNFR1) which sequesters TNF, or the context-dependent regulation where TNFR1 signaling can dampen inflammation through specific mechanisms. Reason: While TNFR1 is primarily pro-inflammatory (through NF-kappaB activation), the soluble form can have anti-inflammatory effects by sequestering TNF. This dual role is context dependent and the negative regulation aspect is not a core function of the receptor. Additionally, some TRAPS-associated variants show paradoxical inflammatory effects suggesting complex regulation. Supporting Evidence: PMID:13130484 Reduced shedding of TNFRSF1A from monocytes was demonstrated in vitro in patients with the T50M and T50K variants
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: IEP evidence for cellular response to mechanical stimulus. Expression pattern evidence indicates TNFR1 expression changes in response to mechanical stimulus. Reason: IEP evidence only shows expression change in response to mechanical stimulus, not that TNFR1 directly mediates the response. This is a weak evidence code and the annotation reflects a secondary observation rather than a core function. Supporting Evidence: PMID:19593445 BAD, a pro-apoptotic protein of the Bcl-2 family, has recently been identified as an integrator of several anti-apoptotic signaling pathways in prostate cancer cells
GO:0045121 membrane raft	IDA PMID:17010968 The shedding activity of ADAM17 is sequestered in lipid raft...	ACCEPT	Summary: IDA evidence for membrane raft localization. Direct experimental evidence supporting TNFR1 partitioning into lipid rafts. Reason: Direct experimental evidence for membrane raft localization, consistent with IBA and IEA annotations. Supporting Evidence: PMID:17010968 metalloproteinase inhibition increases the proportion of ADAM17 substrates (TNF and its receptors TNFR1 and TNFR2) in lipid rafts.
GO:0005515 protein binding	IPI PMID:9115275 MADD, a novel death domain protein that interacts with the t...	MODIFY	Summary: IPI evidence for interaction with MADD (Q8WXG6). Schievella et al. (1997) identified MADD as a death domain protein that interacts with TNFR1 and activates MAP kinase. Reason: Protein binding is uninformative. MADD interaction with the TNFR1 death domain is a specific signaling interaction linking TNFR1 to MAP kinase activation. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:9115275 We have used the yeast interaction trap to isolate a protein, MADD, that associates with the death domain of TNFR1 through its own C-terminal death domain.
GO:0005515 protein binding	IPI PMID:15465831 A death receptor-associated anti-apoptotic protein, BRE, inh...	MODIFY	Summary: IPI evidence for interaction with BABAM2/BRE (Q9NXR7). Li et al. (2004) showed BRE inhibits mitochondrial apoptotic pathway as a death receptor-associated anti-apoptotic protein. Reason: Protein binding is uninformative. The BABAM2 interaction is a specific regulatory interaction in the TNFR1 signaling context. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:15465831 BRE, brain and reproductive organ-expressed protein, was found previously to bind the intracellular juxtamembrane domain of a ubiquitous death receptor, tumor necrosis factor receptor 1 (TNF-R1), and to down-regulate TNF-alpha-induced activation of NF-kappaB.
GO:0005031 tumor necrosis factor receptor activity	TAS PMID:2158863 Molecular cloning and expression of a receptor for human tum...	ACCEPT	Summary: TAS annotation from the original cloning paper by Schall et al. (1990) which described molecular cloning and expression of the human TNF receptor. Reason: TNF receptor activity is the core molecular function. This TAS annotation from the original cloning paper is foundational. Supporting Evidence: PMID:2158863 The TNF receptor (TNF-R) is a 415 amino acid polypeptide with a single membrane-spanning region.
GO:0006954 inflammatory response	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse ortholog. Inflammatory response is a core process. Reason: Consistent with IBA and IEA annotations. Core function.
GO:0019221 cytokine-mediated signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse. Cytokine-mediated signaling is correct for TNFR1 but less specific than TNF-mediated signaling pathway. Reason: TNFR1 is indeed a cytokine receptor that mediates cytokine signaling. While less specific than GO:0033209, this is not incorrect.
GO:0045944 positive regulation of transcription by RNA polymerase II	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse for positive regulation of transcription by RNA polymerase II, reflecting NF-kappaB-driven gene expression. Reason: Downstream consequence of TNFR1 signaling via NF-kappaB. Real but not a core function of the receptor itself.
GO:0050729 positive regulation of inflammatory response	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse for positive regulation of inflammatory response. Reason: TNFR1 signaling via NF-kappaB drives pro-inflammatory gene expression, making positive regulation of inflammatory response a core function. This is more specific than "inflammatory response" and accurately reflects the pro-inflammatory role.
GO:0043123 positive regulation of canonical NF-kappaB signal transduction	IEP PMID:12761501 Large-scale identification and characterization of human gen...	ACCEPT	Summary: IEP evidence from a large-scale screen that identified human genes activating NF-kappaB and MAPK pathways. Reason: While IEP is a weaker evidence code, this annotation is fully consistent with the extensive mechanistic evidence for TNFR1 activation of canonical NF-kappaB signaling. The annotation is correct and supported by numerous other annotations. Supporting Evidence: PMID:12761501 we identified 299 cDNAs that activate the NF-kappaB pathway, and we classified them into 83 genes, including 30 characterized activator genes of the NF-kappaB pathway
GO:0005576 extracellular region	NAS PMID:12189246 Identification of ARTS-1 as a novel TNFR1-binding protein th...	ACCEPT	Summary: NAS annotation for extracellular region. The soluble form of TNFR1 is present in the extracellular region. Reason: Consistent with IDA evidence for extracellular space and IEA for extracellular region. The soluble form (sTNFR1) is well documented in extracellular fluids. Supporting Evidence: PMID:12189246 Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding.
GO:0005576 extracellular region	TAS PMID:1698610 Soluble forms of tumor necrosis factor receptors (TNF-Rs). T...	ACCEPT	Summary: TAS annotation from Nophar et al. (1990) which demonstrated that the TNFR1 cDNA encodes both cell surface and soluble forms of the receptor. Reason: This is one of the earliest demonstrations of the soluble TNFR1 ectodomain in the extracellular region. Supporting Evidence: PMID:1698610 These data suggest that the soluble forms of the TNF-Rs are structurally identical to the extracellular cytokine binding domains of these receptors and are consistent with the notion that the soluble forms are, at least partly, derived from the same transcripts that encode the cell surface receptors.
GO:0005886 plasma membrane	TAS PMID:1698610 Soluble forms of tumor necrosis factor receptors (TNF-Rs). T...	ACCEPT	Summary: TAS annotation from Nophar et al. (1990). Plasma membrane localization for the full-length receptor. Reason: One of the original papers demonstrating TNFR1 at the plasma membrane. Core localization. Supporting Evidence: PMID:1698610 CHO cells transfected with type I TNF-R cDNA produced both cell surface and soluble forms of the receptor.
GO:0005515 protein binding	IPI PMID:11684708 Keratin attenuates tumor necrosis factor-induced cytotoxicit...	MODIFY	Summary: Second IPI entry for interaction with TRADD (Q15628) from the same PMID, curated by UniProt (vs. the IntAct entry above). Reason: Protein binding is uninformative. Duplicate annotation from different curation groups. Proposed replacements: tumor necrosis factor receptor activity Supporting Evidence: PMID:11684708 These results indicate that K18 may sequester TRADD to attenuate interactions between TRADD and activated TNFR1 and moderate TNF-induced apoptosis in simple epithelial cells.
GO:0070266 necroptotic process	TAS PMID:12887920 Induction of TNF receptor I-mediated apoptosis via two seque...	NEW	Summary: TNFR1-mediated signaling is the best-characterized inducer of necroptosis. When caspase-8 is inhibited, RIPK1/RIPK3/MLKL assemble a necrosome downstream of TNFR1 Complex II, executing programmed necrotic cell death. This is a core signaling outcome of TNFR1 activation under specific conditions (PMID:12887920). Reason: Necroptosis is a well-established signaling outcome downstream of TNFR1, particularly when caspase-8 is inhibited. The GO definition of GO:0070266 explicitly references death domain receptor signaling and RIPK1/RIPK3/MLKL dependence. This is missing from the existing annotation set and represents a core function of the receptor under specific signaling contexts. Supporting Evidence: PMID:12887920 TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II).

Core Functions

TNFR1 binds trimeric TNF-alpha and lymphotoxin-alpha via its extracellular cysteine-rich domains (CRD2-CRD3), functioning as the primary signaling receptor for soluble TNF. Upon ligand binding, recruits TRADD via its death domain to nucleate Complex I, activating NF-kappaB and MAPK pathways for pro-inflammatory and pro-survival gene expression.

Molecular Function:

tumor necrosis factor receptor activity

Directly Involved In:

tumor necrosis factor-mediated signaling pathway canonical NF-kappaB signal transduction inflammatory response

Cellular Locations:

cell surface plasma membrane

Supporting Evidence:

PMID:12887920
TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B.
PMID:7758105
Many diverse activities of tumor necrosis factor (TNF) are signaled through TNF receptor 1 (TNFR1). We have identified a novel 34 kDa protein, designated TRADD, that specifically interacts with an intracellular domain of TNFR1 known to be essential for mediating programmed cell death.

When Complex I pro-survival signaling fails (e.g., loss of cIAP or LUBAC activity), TRADD and RIPK1 dissociate from the receptor to form cytosolic Complex II with FADD and caspase-8, triggering extrinsic apoptosis. Under caspase-8 inhibition, RIPK1-RIPK3-MLKL assemble the necrosome for necroptosis.

Molecular Function:

tumor necrosis factor receptor activity

Directly Involved In:

extrinsic apoptotic signaling pathway necroptotic process

Cellular Locations:

plasma membrane

Supporting Evidence:

PMID:12887920
A second complex (complex II) is formed after TRADD and RIP1 associate with FADD and caspase-8, and the modified RIP1 in complex II keeps caspase-8 in an inactive state. When NF-kappa B is activated by complex I, expression of antiapoptotic genes are activated, which are sufficient to block the pro-apoptotic activity of complex II.
PMID:8565075
A FADD mutant lacking its N-terminal 79 amino acids is a dominant-negative inhibitor of TNF-induced apoptosis, but does not inhibit NF-kappa B activation. Thus, these two TNFR1-TRADD signaling cascades appear to bifurcate at TRADD.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:2158863

Molecular cloning and expression of a receptor for human tumor necrosis factor.

Original cloning of TNFR1 (p55) demonstrating TNF receptor activity

"Synthetic DNA probes based on amino acid sequence information were used to isolate cDNA clones encoding a receptor for TNF. The TNF receptor (TNF-R) is a 415 amino acid polypeptide with a single membrane-spanning region."

PMID:7758105

The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation.

Identified TRADD as the primary adaptor for TNFR1 death domain that signals both apoptosis and NF-kappaB activation

"Many diverse activities of tumor necrosis factor (TNF) are signaled through TNF receptor 1 (TNFR1). We have identified a novel 34 kDa protein, designated TRADD, that specifically interacts with an intracellular domain of TNFR1 known to be essential for mediating programmed cell death. Overexpression of TRADD leads to two major TNF-induced responses, apoptosis and activation of NF-kappa B."

PMID:8565075

TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways.

Demonstrated that TRADD-TRAF2 activates NF-kappaB while TRADD-FADD induces apoptosis, defining the bifurcation of TNFR1 signaling at TRADD

"Tumor necrosis factor (TNF) can induce apoptosis and activate NF-kappa B through signaling cascades emanating from TNF receptor 1 (TNFR1). TRADD is a TNFR1-associated signal transducer that is involved in activating both pathways. Here we show that TRADD directly interacts with TRAF2 and FADD, signal transducers that activate NF-kappa B and induce apoptosis, respectively."

PMID:8612133

TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex.

PMID:9115275

MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates mitogen-activated protein kinase.

Identified MADD as a death domain protein interacting with TNFR1, linking the receptor to MAP kinase activation and arachidonic acid release

"We have used the yeast interaction trap to isolate a protein, MADD, that associates with the death domain of TNFR1 through its own C-terminal death domain. MADD interacts with TNFR1 residues that are critical for signal generation and coimmunoprecipitates with TNFR1, implicating MADD as a component of the TNFR1 signaling complex."

PMID:12887920

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

Defined the two-complex model: Complex I (TNFR1/TRADD/RIP1/TRAF2) at the membrane for NF-kappaB activation, and cytosolic Complex II (TRADD/RIP1/FADD/caspase-8) for apoptosis

"The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II)."

PMID:22801493

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis.

Identified MS-associated TNFRSF1A variant causing exon 6 skipping, producing soluble Delta6-TNFR1 isoform. Showed Golgi membrane localization of TNFR1

"While FL-TNFR1 localizes to the Golgi apparatus, Δ6-TNFR1 demonstrated a more diffuse intracellular distribution (Fig. 2), consistent with the absence of the Golgi-retention motif."

PMID:9435233

The type 1 receptor (CD120a) is the high-affinity receptor for soluble tumor necrosis factor.

PMID:24966471

Tumor necrosis factor alpha - a link between neuroinflammation and excitotoxicity.

PMID:25816133

Tumor necrosis factor disrupts claudin-5 endothelial tight junction barriers in two distinct NF-κB-dependent phases.

PMID:13130484

Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes.

Characterized TRAPS-associated TNFRSF1A variants and showed soluble TNFR1 in extracellular space

"Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes."

PMID:17010968

The shedding activity of ADAM17 is sequestered in lipid rafts.

PMID:15465831

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

PMID:24130170

SH3RF2 functions as an oncogene by mediating PAK4 protein stability.

PMID:10848577

Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappaB activation.

PMID:1698610

Soluble forms of tumor necrosis factor receptors (TNF-Rs). The cDNA for the type I TNF-R, cloned using amino acid sequence data of its soluble form, encodes both the cell surface and a soluble form of the receptor.

Demonstrated that TNFR1 cDNA encodes both membrane-bound and soluble receptor forms

"CHO cells transfected with type I TNF-R cDNA produced both cell surface and soluble forms of the receptor."

PMID:21410936

Signal pathways in astrocytes activated by cross-talk between of astrocytes and mast cells through CD40-CD40L.

PMID:23382219

Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.

PMID:9915703

Prevention of constitutive TNF receptor 1 signaling by silencer of death domains

Identified BAG4/SODD as a silencer that binds the TNFR1 death domain to prevent spontaneous signaling

"Tumor necrosis factor receptor type 1 (TNF-R1) contains a cytoplasmic death domain that is required for the signaling of TNF activities such as apoptosis and nuclear factor kappa B (NF-kappaB) activation. Normally, these signals are generated only after TNF-induced receptor aggregation."

file:human/TNFRSF1A/TNFRSF1A-deep-research-falcon.md

Deep research synthesis of TNFRSF1A literature

PMID:11684708

Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD.

PMID:14743216

A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.

PMID:16611992

Competitive control of independent programs of tumor necrosis factor receptor-induced cell death by TRADD and RIP1.

PMID:18022363

IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.

PMID:19524513

Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation.

PMID:19641494

Riboflavin kinase couples TNF receptor 1 to NADPH oxidase.

PMID:19781631

Proteinase-activated receptor-2 mediated inhibition of TNFalpha-stimulated JNK activation - A novel paradigm for G(q/11) linked GPCRs.

PMID:20080539

The Polycomb group protein EED couples TNF receptor 1 to neutral sphingomyelinase.

PMID:20103630

Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity.

PMID:22028622

Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor α-induced necroptosis.

PMID:22817896

The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis.

PMID:23955153

Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains.

PMID:24070898

Progranulin directly binds to the CRD2 and CRD3 of TNFR extracellular domains.

PMID:25241761

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

PMID:25911380

The seventh zinc finger motif of A20 is required for the suppression of TNF-α-induced apoptosis.

PMID:2848815

Human tumor necrosis factor-alpha receptor. Purification by immunoaffinity chromatography and initial characterization.

PMID:32822567

A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions.

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:36179048

Novel biochemical, structural, and systems insights into inflammatory signaling revealed by contextual interaction proteomics.

PMID:8621670

Systematic mutational analysis of the death domain of the tumor necrosis factor receptor 1-associated protein TRADD.

PMID:8943045

The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:8387891

Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation.

PMID:33824270

Membrane lymphotoxin-α(2)β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist.

PMID:8985253

RAIDD is a new 'death' adaptor molecule.

PMID:24440909

A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis.

PMID:19593445

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

PMID:12761501

Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways.

PMID:12189246

Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding.

Reactome:R-HSA-3371353

Reactome pathway - TNFR1-induced signaling

Reactome:R-HSA-5357757