Gene Report

Basic Information

Approved Symbol	TNFRSF1A
Approved Name	tumor necrosis factor receptor superfamily, member 1A
Previous Symbol	TNFR1
Symbol Alias	TNF-R, TNFAR, TNFR60, TNF-R-I, CD120a, TNF-R55
Location	12p13.2
Position	chr12:6437923-6451283 (-)
External Links	Entrez Gene: 7132 Ensembl: ENSG00000067182 UCSC: uc001qnu.3 HGNC ID: 11916
No. of Studies (Positive/Negative)	1(1/0)
Type	Literature-origin; Protein mapped

Positive relationships between TNFRSF1A and MDD (count: 0)

Positive relationships between TNFRSF1A and other components at different levels (count: 2)

Genetic/epigenetic locus					Protein and other molecule			Cell and molecular pathway			Neural system			Cognition and behavior		Symptoms and signs			Environment

Name in Literature	Level	Approved Name (Name in Literature)	Type	Reference	Research Type	Relation Description
Name in Literature	Related Components
TNFR1		Depression-like behaviors from animal model(depressive-like behavior)	cognition and behavior	Simen BB, 2006	animal model	We show that deletion of either TNFR1 or TNFR2 leads to an a...... We show that deletion of either TNFR1 or TNFR2 leads to an antidepressant-like response in the forced swim test More...
TNFR1		Conditioned responses (CRs)(decreased fear conditioning)	cognition and behavior	Simen BB, 2006	animal model	deletion of TNFR1 leads to decreased fear conditioning. deletion of TNFR1 leads to decreased fear conditioning.

Positive relationship network of TNFRSF1A in MK4MDD

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Note:
1. The different color of the nodes denotes the level of the nodes.

Genetic/Epigenetic Locus	Protein and Other Molecule	Cell and Molecular Pathway	Neural System	Cognition and Behavior	Symptoms and Signs	Environment	MDD

2. Besides the component related relationships from literature, gene mapped protein and protein mapped gene are also shown in the network. If the mapped gene or protein is not from literature, square node would be used instead of Circle node. Accordingly, the relationship is marked with dot line.
2. User can drag the nodes to rearrange the layout of the network. Click the node will enter the report page of the node. Right-click will show also the menus to link to the report page of the node and remove the node and related edges. Hover the node will show the level of the node and hover the edge will show the evidence/description of the edge.
3. The network is generated using Cytoscape Web

Negative relationships between TNFRSF1A and MDD (count: 0)

Negative relationships between TNFRSF1A and other components at different levels (count: 1)

Genetic/epigenetic locus					Protein and other molecule			Cell and molecular pathway			Neural system			Cognition and behavior		Symptoms and signs			Environment

Name in Literature	Level	Approved Name (Name in Literature)	Type	Reference	Research Type	Statistical Result	Relation Description
Name in Literature	Related Components
TNFR1		Anxiety-like behaviors from animal model(anxiety-like behavior)	cognition and behavior	Simen BB, 2006	animal model		There were no differences in behavior in anxiety tests for e...... There were no differences in behavior in anxiety tests for either null mutant. More...

TNFRSF1A related SNPs in MK4MDD (count: 0)

TNFRSF1A related proteins in MK4MDD (count: 1)

Approved Name	UniportKB	No. of Studies (Positive/Negative)	Source
Tumor necrosis factor receptor superfamily member 1A	P19438	1(1/0)	Literature-origin

TNFRSF1A related GO terms (count: 43)

ID	Name	Type	Evidence
Literature-origin GO terms
GO:0006954	inflammatory response	biological process	ISS
GO:0006915	apoptotic process	biological process	TAS

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0030424	axon	cellular component	IEA
GO:0050729	positive regulation of inflammatory response	biological process	ISS
GO:0042981	regulation of apoptotic process	biological process	IEA
GO:0045471	response to ethanol	biological process	IEA
GO:0001666	response to hypoxia	biological process	IEA
GO:0050728	negative regulation of inflammatory response	biological process	IMP[13130484]
GO:0071260	cellular response to mechanical stimulus	biological process	IEP[19593445]
GO:0032496	response to lipopolysaccharide	biological process	IEA
GO:0002020	protease binding	molecular function	IEA
GO:0005634	nucleus	cellular component	IEA
GO:0016101	diterpenoid metabolic process	biological process	IEA
GO:0010629	negative regulation of gene expression	biological process	IEA
GO:0045766	positive regulation of angiogenesis	biological process	IEA
GO:0043200	response to amino acid stimulus	biological process	IEA
GO:0033160	positive regulation of protein import into nucleus, translocation	biological process	IEA
GO:0006693	prostaglandin metabolic process	biological process	IEA
GO:0032715	negative regulation of interleukin-6 production	biological process	IEA
GO:0043279	response to alkaloid	biological process	IEA
GO:0009986	cell surface	cellular component	IEA
GO:0045121	membrane raft	cellular component	IDA[17010968]
GO:0043234	protein complex	cellular component	IEA
GO:0043120	tumor necrosis factor binding	molecular function	IEA
GO:0005886	plasma membrane	cellular component	TAS
GO:0005031	tumor necrosis factor-activated receptor activity	molecular function	TAS[2158863]
GO:0033013	tetrapyrrole metabolic process	biological process	IEA
GO:0005515	protein binding	molecular function	IPI
GO:0071392	cellular response to estradiol stimulus	biological process	IEA
GO:0019221	cytokine-mediated signaling pathway	biological process	ISS
GO:0043123	positive regulation of I-kappaB kinase/NF-kappaB cascade	biological process	IEP[12761501]
GO:0051291	protein heterooligomerization	biological process	IEA
GO:0000139	Golgi membrane	cellular component	IDA
GO:0009812	flavonoid metabolic process	biological process	IEA
GO:0005615	extracellular space	cellular component	IDA[13130484]
GO:0005576	extracellular region	cellular component	NAS[12189246]
GO:0005887	integral to plasma membrane	cellular component	TAS[1698610]
GO:0042511	positive regulation of tyrosine phosphorylation of Stat1 protein	biological process	IMP
GO:0042742	defense response to bacterium	biological process	IEA
GO:0019048	virus-host interaction	biological process	IEA
GO:0045944	positive regulation of transcription from RNA polymerase II promoter	biological process	IMP; ISS
GO:0032403	protein complex binding	molecular function	IEA
GO:0032760	positive regulation of tumor necrosis factor production	biological process	IEA

TNFRSF1A related KEGG pathways (count: 6)

ID	Name	Brief Description	Full Description
Gene mapped KEGG pathways
hsa05010	alzheimers disease	Alzheimer's disease	Alzheimer's disease (AD) is a chronic disorder that slowly d...... Alzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. The extracellular Abeta oligomers may activate caspases through activation of cell surface death receptors. Alternatively, intracellular Abeta may contribute to pathology by facilitating tau hyper-phosphorylation, disrupting mitochondria function, and triggering calcium dysfunction. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specifically the more amyloidogenic form, Abeta42. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress. More...
hsa05014	amyotrophic lateral_sclerosis_als	Amyotrophic lateral sclerosis (ALS)	Amyotrophic lateral sclerosis (ALS) is a progressive, lethal...... Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. Mutant superoxide dismutase 1 (SOD1), as seen in some familial amyotrophic lateral sclerosis (FALS) cases, may be toxic because it is unstable, forming aggregates in the motor neuron cytoplasm, axoplasm and mitochondria. Within mitochondria, mutant SOD1 may interfere with the anti-apoptotic function of Bcl-2, affect mitochondrial import by interfering with the translocation machinery (TOM/TIM), and generate toxic free radicals (ROS) via aberrant superoxide chemistry. These changes may then result in abnormal mitochondrial energy metabolism, Ca2+ handling, and release of pro-apoptotic factors. Reactive oxygen species (ROS), produced within mitochondria, inhibit the function of EAAT2, the main glial glutamate transporter protein, responsible for most of the reuptake of synaptically released glutamate. Glutamate excess causes neurotoxicity by increasing intracellular calcium, which enhances oxidative stress and mitochondrial damage. Mutant SOD1 can also trigger oxidative reactions by various means including by increasing levels of peroxynitrite, which can then cause damage through the formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. Nitration may target neurofilament proteins, disrupting their phosphorylation and affecting axonal transport. Collectively, these mechanisms (or a combination thereof) are predicted to disturb cellular homeostasis (within glial and/or motor neurons), ultimately triggering motor neuron death. More...
hsa04010	mapk signaling_pathway	MAPK signaling pathway	The mitogen-activated protein kinase (MAPK) cascade is a hig...... The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli. More...
hsa04920	adipocytokine signaling_pathway	Adipocytokine signaling pathway	Increased adipocyte volume and number are positively correla...... Increased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin. Leptin is an important regulator of energy intake and metabolic rate primarily by acting at hypothalamic nuclei. Leptin exerts its anorectic effects by modulating the levels of neuropeptides such as NPY, AGRP, and alpha-MSH. This leptin action is through the JAK kinase, STAT3 phosphorylation, and nuclear transcriptional effect. Adiponectin lowers plasma glucose and FFAs. These effects are partly accounted for by adiponectin-induced AMPK activation, which in turn stimulates skeletal muscle fatty acid oxidation and glucose uptake. Furthermore, activation of AMPK by adiponectin suppresses endogenous glucose production, concomitantly with inhibition of PEPCK and G6Pase expression. The proinflammatory cytokine TNFalpha has been implicated as a link between obesity and insulin resistance. TNFalpha interferes with early steps of insulin signaling. Several data have shown that TNFalpha inhibits IRS1 tyrosine phosphorylation by promoting its serine phosphorylation. Among the serine/threonine kinases activated by TNFalpha, JNK, mTOR and IKK have been shown to be involved in this phosphorylation. More...
hsa04210	apoptosis	Apoptosis	Apoptosis is a genetically controlled mechanisms of cell dea...... Apoptosis is a genetically controlled mechanisms of cell death involved in the regulation of tissue homeostasis. The 2 major pathways of apoptosis are the extrinsic (Fas and other TNFR superfamily members and ligands) and the intrinsic (mitochondria-associated) pathways, both of which are found in the cytoplasm. The extrinsic pathway is triggered by death receptor engagement, which initiates a signaling cascade mediated by caspase-8 activation. Caspase-8 both feeds directly into caspase-3 activation and stimulates the release of cytochrome c by the mitochondria. Caspase-3 activation leads to the degradation of cellular proteins necessary to maintain cell survival and integrity. The intrinsic pathway occurs when various apoptotic stimuli trigger the release of cytochrome c from the mitochondria (independently of caspase-8 activation). Cytochrome c interacts with Apaf-1 and caspase-9 to promote the activation of caspase-3. Recent studies point to the ER as a third subcellular compartment implicated in apoptotic execution. Alterations in Ca2+ homeostasis and accumulation of misfolded proteins in the ER cause ER stress. Prolonged ER stress can result in the activation of BAD and/or caspase-12, and execute apoptosis. More...
hsa04060	cytokine cytokine_receptor_interaction	Cytokine-cytokine receptor interaction	Cytokines are soluble extracellular proteins or glycoprotein...... Cytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell growth, differentiation, cell death, angiogenesis, and development and repair processes aimed at the restoration of homeostasis. Cytokines are released by various cells in the body, usually in response to an activating stimulus, and they induce responses through binding to specific receptors on the cell surface of target cells. Cytokines can be grouped by structure into different families and their receptors can likewise be grouped. More...

TNFRSF1A related BioCarta pathways (count: 10)

ID	Name	Brief Description	Full Description
Gene mapped BioCarta pathways
NFKB_PATHWAY	nfkb pathway	NF-kB Signaling Pathway	Nuclear factor kB (NF-kB) is a nuclear transcription factor ...... Nuclear factor kB (NF-kB) is a nuclear transcription factor that regulates expression of a large number of genes that are critical for the regulation of apoptosis, viral replication, tumorigenesis, inflammation, and various autoimmune diseases. The activation of NF-kB is thought to be part of a stress response as it is activated by a variety of stimuli that include growth factors, cytokines, lymphokines, UV, pharmacological agents, and stress. In its inactive form, NF-kB is sequestered in the cytoplasm, bound by members of the IkB family of inhibitor proteins, which include IkBa, IkBb, IkBg, and IkBe. The various stimuli that activate NF-kB cause phosphorylation of IkB, which is followed by its ubiquitination and subsequent degradation. This results in the exposure of the nuclear localization signals (NLS) on NF-kB subunits and the subsequent translocation of the molecule to the nucleus. In the nucleus, NF-kB binds with a consensus sequence (5'GGGACTTTCC-3') of various genes and thus activates their transcription. IkB proteins are phosphorylated by IkB kinase complex consisting of at least three proteins; IKK1/IKKa, IKK2/IKKb, and IKK3/IKKg. These enzymes phosphorylate IkB leading to its ubiquitination and degradation. Tumor necrosis factor (TNF) which is the best-studied activator binds to its receptor and recruits a protein called TNF receptor death domain (TRADD). TRADD binds to the TNF receptor-associated factor 2 (TRAF-2) that recruits NF-kB-inducible kinase (NIK). Both IKK1 and IKK2 have canonical sequences that can be phosphorylated by the MAP kinase NIK/MEKK1 and both kinases can independently phosphorylate IkBa or IkBb. TRAF-2 also interacts with A20, a zinc finger protein whose expression is induced by agents that activate NF-kB. A20 functions to block TRAF2-mediated NF-kB activation. A20 also inhibits TNF and IL-1 induced activation of NF-kB suggesting that it may act as a general inhibitor of NF-kB activation. More...
KERATINOCYTE_PATHWAY	keratinocyte pathway	Keratinocyte Differentiation	The epidermis, which provides a protective barrier that unde...... The epidermis, which provides a protective barrier that undergoes a constant renewal, is a multi-layered tissue with the proliferating cells located in the basal layer. As cells leave the basal layer the underog significant differentiation, biochemical and morphological remodeling. The final differentiation results in the formation of corneocytes. In vitro keratinocytes mimic this process. Several genes mark keratinocyte specific differentiation. Among the most frequently tracked markers are Transglutaminase, Cystatin and Involucrin. The keratinocyte differentiation studies have identified and provided significant detail regarding the involvement of three of the 4 major MAP kinase pathways from several diverse stimuli such as EGF, FAS, TNF and Calicium influx. The p38 cascade is represented twice since both p38alpha (p38) and p38delta (MAPK13) are involved. The keratinocyte differentiation cascased also provide for detailed study of the functions of individual PKC isoforms. It is interesting to note the contrasting functions of the PKC isoforms in this process. In recent studies it has been determined that the cPKC (conventional/classical Protein Kinase C) isoforms, which are calcium-, phospholipid-, and diacylglycerol-dependent are inhibitory where as the nPKC (novel Protein Kinase C) isoforms which are calcium independent are stimulatory for keratinocyte differentiation markers. On the right hand side is an earlier step showing the upregulation loop of TRAF2. This step occurs prior to the activation os ASK1 and the p38 cascade. More...
HIVNEF_PATHWAY	hivnef pathway	HIV-I Nef: negative effector of Fas and TNF	HIV infection leads to drastic declines in CD4 T helper cell...... HIV infection leads to drastic declines in CD4 T helper cells, in part through apoptosis of uninfected cells. Apoptosis of uninfected cells may be induced through the expression of Fas ligand on the surface of HIV-infected cells, stimulating the Fas-dependent apoptotic pathway in cells that come in contact with infected cells. The NEF protein expressed by HIV may play induce the expression of Fas-ligand by infected cells. If this is the case, then a question that arises is how infected cells themselves escape Fas-mediated apoptosis. The NEF protein appears to play a role in this process as well. NEF interacts with the ASK1 kinase (apoptosis signal-regulating kinase) involved in apoptotic signaling by TNF and Fas-ligand. Interaction of NEF with ASK1 prevents phosphorylation of downstream MAP kinases and JNK kinases involved in apoptotic signaling. More...
RELA_PATHWAY	rela pathway	Acetylation and Deacetylation of RelA in The Nucleus
TID_PATHWAY	tid pathway	Chaperones modulate interferon Signaling Pathway	Signaling by interferon-gamma stimulates anti-viral response...... Signaling by interferon-gamma stimulates anti-viral responses and tumor suppression through the heterodimeric interferon-gamma receptor. Signaling is initiated by binding of interferon-gamma to its receptor, activating the receptor-associated JAK2 tyrosine kinase to phosphorylate STAT transcription factors that activate interferon responsive genes. Molecular chaperones that modulate or alter protein folding interact with different components of the interferon signaling pathway. One chaperone that modulates interferon signaling is hTid-1, a member of the DnaJ family of chaperones and a cochaperone for the heat shock protein Hsp70, another molecular chaperone. hTid-1 was found in a two-hybrid screen to bind to JAK2 and also to interact with the interferon-gamma receptor. In addition, hTid-1 and JAK2 also interact with Hsp70. Overexpression of hTid-1 represses transcriptional activation by interferon-gamma and Hsp70 dissociates from these proteins when interferon is added to cells, suggesting that Hsp70 holds Jak2 in an inactive conformation prior to ligand activation, and is released in the presence of agonist to allow the activation of Jak-2 and downstream pathways. hTid-1 and Hsp-70 interact with other signaling proteins as well. One of this is Tax, a protein encoded by the HTLV-1 virus that binds to hTid-1. hTid-1 also represses NF-kB activation by blocking the phosphorylation and inactivation of I-kappaB by the IkappaB kinase beta. Hsp70 plays a significant role in protein unfolding for entry into mitochondria and also interacts with tumor suppressor gene products to produce their anti-proliferative activity. One of the actions of interferon is to induce apoptosis of infected target cells, in part through a mitochondrial dependent mechanism. An interaction between interferon signaling and Hsp70 may alter this mitochondrial apoptosis pathway, perhaps playing a role in interferon-mediated apoptosis of infected or transformed cells. The HTLV-1 Tax protein that interacts with Hsp70 blocks mitochondrial induced apoptosis, providing a protection against interferon-mediated cellular defenses. More...
STRESS_PATHWAY	stress pathway	TNF/Stress Related Signaling	TNF acts on several different signaling pathways through two...... TNF acts on several different signaling pathways through two cell surface receptors, TNFR1 and TNFR2 to regulate apoptotic pathways, NF-kB activation of inflammation, and activate stress-activated protein kinases (SAPKs). Interaction of TNFR1 with TRADD leads to activation of NF-kB and apoptosis pathways, while interaction with TRAF2 has generally been thought to be involved in stress kinase and NF-kB activation but is not required for TNF to induce apoptosis. Activation of NF-kB is mediated by TRAF2 through the NIK kinase and also by RIP but the observation that TNF activates NF-kB in mice lacking TRAF2 indicates that TRAF-2 does not play an essential role in this process. Stress-activated protein kinases, also called JNKs, are a family of map kinases activated by cellular stress and inflammatory signals. Binding of TNF to the TNFR1 receptor activates the germinal center kinase (GCK) through the TNF adaptor Traf2, activating the map kinase MEKK1. Both GCK and MEKK1 interact with Traf2, and GCK is required for MEKK1 activation by TNF, but GCK kinase activity does not appear to be required for MEKK1 activation. Instead, GCK activates MEKK1 by causing MEKK1 oligomerization and autophosphorylation. Tank increases the affinity of Traf2 for GCK to increase Map kinase activation by TNF. Once activated, MEKK1 stands at the top of a map kinase pathways leading to transcriptional regulation, including JNK phosphorylation of c-Jun to stimulate transcriptional activation by AP-1, a heterodimer of c-jun and fos or ATF proteins. The activation of the p38 Map kinase also contributes to AP-1 activation leading to the transcriptional activation of many stress and growth related genes. RIP has been suggested as a component of the p38 pathway in addition to playing a role in NF-kB activation. MEKK1 knockout mice support the role of MEKK1 in JNK activation in some cells but did not support MEKK1 dependent activation of NF-kB. Alternative redundant mechanisms may obscure the role of MEKK1 in NF-kB mechanisms. TNF activation of stress kinase pathways and downstream transcription factors may help to modulate the apoptotic pathways also activated by TNF. More...
PML_PATHWAY	pml pathway	Regulation of transcriptional activity by PML	The PML nuclear bodies are ring-shaped nuclear substructures...... The PML nuclear bodies are ring-shaped nuclear substructures associated with the regulation of transcription, transformation, cell growth, and apoptosis and are characterized by the presence of the protein PML. The activities of PML as a tumor suppressor and apoptosis inducing factor are exerted through the numerous proteins it interacts with in the PML-nuclear bodies including the tumor suppressor p53. DNA damage induced activation of p53-dependent apoptosis requires PML. PML acts as a coactivator for p53 and increases acetylation of p53 by the transcriptional coactivator CBP. This acetylation of p53 is reversed by the deacetylase SirT1, the human homolog of the yeast gene Sir2, and this deacetylation opposes the transcriptional activation of p53. The tumor suppressor Rb also interacts with the PML nuclear body, increasing transcriptional repression of genes involved in cell cycle progression, suggesting that PML may affect cellular transformation through more than one mechanism. PML interacts directly with Ubc9, which modifies PML through the attachment of the ubiquitin-like peptide Sumo-1. Sumo-1 modification of PML is not necessary for the nuclear bodies to form, but may affect the recruitment of proteins that interact with PML. PML is involved in non-p53 mediated apoptotic pathways, such as DAXX-mediated apoptosis induced by Fas and TNF and regulates the transcriptional repressor activity of Daxx. The sequestration of Daxx by the PML nuclear bodies relieves the repression of other transcription factors like Pax3 by Daxx. Tumor suppression by PML may in general involve the formation of specific regulatory transcription complexes, including those with DAXX, p53 and CBP. Factors that affect the assembly of PML into the PML nuclear bodies affect the proliferation and transformation of cells. Viral early proteins can interact with PML to disrupt the nuclear bodies, allowing increased proliferation of cells and reduced apoptosis, good conditions for DNA virus infection. Another factor that disrupts the formation of PML nuclear bodies is a translocation between the PML and RAR-alpha genes found in acute promyelocytic leukemia (APL) patients. Binding of retinoic acid to the RAR-alpha steroid hormone receptor activates transcription of retinoic-acid responsive genes. The translocation found in APL patients creates two chimeric proteins, RARalpha-PML and PML-RARalpha. Retinoic acid given to APL patients causes the reappearance of nuclear bodies, and the reversal of cellular transformation, effecting a cure for these patients. More...
SODD_PATHWAY	sodd pathway	SODD/TNFR1 Signaling Pathway	The tumor necrosis factor (TNF) receptor superfamily contain...... The tumor necrosis factor (TNF) receptor superfamily contains several members with homologous cytoplasmic domains known as death domains (DD). The intracellular DD are important in initiating apoptosis and other signaling pathways following ligand binding by the receptors.1 In the absence of ligand, DD-containing receptors are maintained in an inactive state. TNF RI contains a cytoplasmic DD required for signaling pathways associated with apoptosis and NF-kB activation.2,3 Jiang et al.4 identified a widely expressed 60 kDa protein, named SODD (silencer of death domains), associated with the DD of TNF RI and DR3. Overexpression of SODD suppresses TNF-induced cell death and NF-kB activation demonstrating its role as a negative regulatory protein for these signaling pathways. TNF-induced receptor trimerization aggregates the DD of TNF RI and recruits the adapter protein TRADD.3,5 This in turn promotes the recruitment of the DD-containing cytoplasmic proteins FADD, TRAF2 and RIP to form an active TNF RI signaling complex (Figure 1A).6-9 In contrast, SODD acts as a silencer of TNF RI signaling and does not interact with TRADD, FADD, or RIP (Figure 1B).4 It is associated with the DD of TNF RI and maintains TNF RI in an inactive, monomeric state. TNF-induced aggregation of TNF RI promotes the disruption of the SODD-TNF RI complex. SODD does not interact with the DD of other TNF receptor superfamily members such as Fas, DR4, DR5, or TNF RII. SODD association with TNF RI may represent a general model for the prevention of spontaneous TNF signaling by other DD-containing receptors. More...
CERAMIDE_PATHWAY	ceramide pathway	Ceramide Signaling Pathway	Over 1,000 papers and reviews have been written about the ro...... Over 1,000 papers and reviews have been written about the role of ceramide in the production of programmed cell death or apoptosis. Ceramide is a sphingosine-based lipid-signaling molecule involved in the regulation of cellular differentiation, proliferation, and apoptosis. This diagram represents some of the current understanding of the cascades that couple ceramide to specific signaling pathways. These cascades illustrate that ceramide can be a growth stimulus or proapototic signal. The ultimate ceramide action is determined within the context of other stimuli and by the subcellular topology of its production and is cell-type specific. There are 2 forms of sphingomyelinase, acid (acid-sphingomyelinase:A-SMase) and neutral (neutral-sphingomyelinase N-SMase), that can produce ceramide. TNF-alpha can stimulate either form of sphingomyelinase as can other death receptors. Different domanis of TNF-alpha stimulate the different Smases. N-SMase stimulation is enhanced by the receptor for activated-C kinase 1 (RACK1). The activity of each form is dependent on the local intracellular pH. In the illustration the forms are seperated to reduce confusion however ceramide produced by either method can stimulate either cascade depending on the presence of specific co-factors and activators. A-SMase has been recognized as one of the required molecules to mediate proapoptotic signalling in cell death induced by a diverse array of stresses such as H2O2, Heat, UV exposure and Radiation. ROS generation in mitochondria activates caspase-3 via cooperation of cytochrome c, Aif and caspase-9 and stimulates or increases ceramide generation through A-SMase in a proaptotic activation cycle. Caspase-3 further increases its own activation by proteolytically cleaving ceramide inhibited catalase which is an inhibitor of ROS generation. Ceramide-activated protein kinase(CARK) also known as Kinase Supressor of RAS (KSR) activity is in some cases the switch point in the balance between proapoptotic and antiapoptotic signals and is also cell-type specific. In endothelial cells for example the activation of KSR is required for apoptosis. In contrast in epithelial cells activation of KSR is required for cell proliferation. An additional switch point is the availability of Bad in the cell. Activation of KSR leads to further mitocondrial stimulation or association with RAS and activation of the Raf1 cascade leading to proliferation or differentiation. More...
TNFR1_PATHWAY	tnfr1 pathway	TNFR1 Signaling Pathway	TNFR1 (a.k.a. p55, CD120a) is the receptor for TNF(alpha) an...... TNFR1 (a.k.a. p55, CD120a) is the receptor for TNF(alpha) and also will bind TNF(beta). Upon binding TNF(alpha) a TNFR1+ cell is triggered to undergo apoptosis. This critical regulatory process is accomplished by activating the proteolytic caspase cascade that results in the degradation of many critical cellular proteins. More...

TNFRSF1A related Reactome pathways (count: 2)

ID	Name	Description
Gene mapped Reactome pathways
REACT_1619	death receptor_signalling	The death receptors, all cell-surface receptors, begin the p...... The death receptors, all cell-surface receptors, begin the process of caspase activation. The common feature of these type 1 transmembrane proteins is the death-domain a conserved cytoplasmic motif found on all of the three receptors (FAS/CD95, TNF-receptor, and TRAIL-receptor) that binds the Fas-associated protein with death domain (FADD) More...
REACT_578	apoptosis	Apoptosis is a distinct form of cell death that is functiona...... Apoptosis is a distinct form of cell death that is functionally and morphologically different from necrosis. Nuclear chromatin condensation, cytoplasmic shrinking, dilated endoplasmic reticulum, and membrane blebbing characterize apoptosis in general. Mitochondria remain morphologically unchanged. In 1972 Kerr et al introduced the concept of apoptosis as a distinct form of cell-death, and the mechanisms of various apoptotic pathways are still being revealed today. The two principal pathways of apoptosis are (1) the Bcl-2 inhibitable or intrinsic pathway induced by various forms of stress like intracellular damage, developmental cues, and external stimuli and (2) the caspase 8/10 dependent or extrinsic pathway initiated by the engagement of death receptors The caspase 8/10 dependent or extrinsic pathway is a death receptor mediated mechanism that results in the activation of caspase-8 and caspase-10. Activation of death receptors like Fas/CD95, TNFR1, and the TRAIL receptor is promoted by the TNF family of ligands including FASL (APO1L OR CD95L), TNF, LT-alpha, LT-beta, CD40L, LIGHT, RANKL, BLYS/BAFF, and APO2L/TRAIL. These ligands are released in response to microbial infection, or as part of the cellular, humoral immunity responses during the formation of lymphoid organs, activation of dendritic cells, stimulation or survival of T, B, and natural killer (NK) cells, cytotoxic response to viral infection or oncogenic transformation. The Bcl-2 inhibitable or intrinsic pathway of apoptosis is a stress-inducible process, and acts through the activation of caspase-9 via Apaf-1 and cytochrome c. The rupture of the mitochondrial membrane, a rapid process involving some of the Bcl-2 family proteins, releases these molecules into the cytoplasm. Examples of cellular processes that may induce the intrinsic pathway in response to various damage signals include: auto reactivity in lymphocytes, cytokine deprivation, calcium flux or cellular damage by cytotoxic drugs like taxol, deprivation of nutrients like glucose and growth factors like EGF, anoikis, transactivation of target genes by tumor suppressors including p53. In many non-immune cells, death signals initiated by the extrinsic pathway are amplified by connections to the intrinsic pathway. The connecting link appears to be the truncated BID (tBID) protein a proteolytic cleavage product mediated by caspase-8 or other enzymes. More...

TNFRSF1A related interactors from protein-protein interaction data in HPRD (count: 44)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
TNFRSF1A	ERN1	No	in vivo	16680093
TNFRSF1A	TNF	Yes	in vitro;in vivo	10634209 , 14743216 , 19084540
TNFRSF1A	TNFSF13	No	in vitro	10706119
TNFRSF1A	LTB	No	in vitro	7995952
TNFRSF1A	TRAF1	No	in vivo	8565075
TNFRSF1A	RIPK1	No	in vivo;yeast 2-hybrid	8612133
TNFRSF1A	JAK2	No	in vitro;in vivo	9510175
TNFRSF1A	TRPC4AP	No	in vivo	14585990
TNFRSF1A	TNFRSF25	Yes	yeast 2-hybrid	8934525
TNFRSF1A	MADD	No	in vitro	9115275
TNFRSF1A	TRADD	No	in vitro;in vivo;yeast 2-hybrid	7758105 , 8565075 , 8612133 , 11934887 , 8621670
TNFRSF1A	TNFRSF1A	Yes	in vitro;yeast 2-hybrid	9126987 , 8077196
TNFRSF1A	IKBKB	No	in vitro	10755617
TNFRSF1A	RASSF1	No	in vivo	15949439
TNFRSF1A	MYOC	No	yeast 2-hybrid	16289162
TNFRSF1A	RIPK3	No	in vivo	10339433
TNFRSF1A	LTA	Yes	in vivo	8387891
TNFRSF1A	PTK2	No	in vivo	12748169
TNFRSF1A	NSMAF	No	in vitro;in vivo;yeast 2-hybrid	8808629
TNFRSF1A	RIPK2	No	in vivo	9642260
TNFRSF1A	MOAP1	No	in vivo	15949439
TNFRSF1A	CHUK	No	in vivo	10755617
TNFRSF1A	UBE2I	No	in vitro;yeast 2-hybrid	9563508
TNFRSF1A	FANCD2	No	in vitro	14743216
TNFRSF1A	PSMD2	No	in vitro;yeast 2-hybrid	7601280 , 9126987
TNFRSF1A	IKBKG	No	in vivo	10755617
TNFRSF1A	DAPK1	No	in vitro;in vivo	12911633
TNFRSF1A	CASP7	No	in vitro	11755217
TNFRSF1A	HSP90AA1	No	in vitro	7876093
TNFRSF1A	PTPN11	No	in vivo	11786908
TNFRSF1A	SUMO1	No	in vitro;in vivo;yeast 2-hybrid	10187798 , 8906799
TNFRSF1A	TRAP1	No	in vitro;yeast 2-hybrid	7876093
TNFRSF1A	PIP4K2B	No	in vitro;in vivo	9038203 , 9753329
TNFRSF1A	MAPK1	Yes	in vitro	11606045
TNFRSF1A	PTPN6	Yes	in vivo	11786908
TNFRSF1A	ERAP1	No	in vivo	12189246
TNFRSF1A	CASP10	No	in vitro	11098060
TNFRSF1A	SYK	No	in vivo	16291755
TNFRSF1A	BAG4	No	in vitro;in vivo;yeast 2-hybrid	9915703 , 11909948
TNFRSF1A	JAK1	No	in vitro;in vivo	11801527
TNFRSF1A	GRB2	No	in vivo	10359574
TNFRSF1A	STAT1	No	in vitro	10848577
TNFRSF1A	GNB2L1	No	in vitro	12391233
TNFRSF1A	TRAF2	No	in vivo	8565075

Gene Report

Literature-origin GO terms

Gene mapped GO terms

Gene mapped KEGG pathways

Gene mapped BioCarta pathways

Gene mapped Reactome pathways