scholarly journals Dynamics of RASSF1A/MOAP-1 Association with Death Receptors

2008 ◽  
Vol 28 (14) ◽  
pp. 4520-4535 ◽  
Author(s):  
Caitlin J. Foley ◽  
Holly Freedman ◽  
Sheryl L. Choo ◽  
Christina Onyskiw ◽  
Nai Yang Fu ◽  
...  
Keyword(s):  
Tumor Necrosis Factor Receptor ◽  
Death Receptor ◽  
Death Receptors ◽  
Tumor Formation ◽  
Receptor Interaction ◽  
Binding Motif ◽  
Death Domain ◽  
Interacting Protein ◽  
Receptor Complexes ◽  
Tnf Α

ABSTRACT RASSF1A is a tumor suppressor protein involved in death receptor-dependent apoptosis utilizing the Bax-interacting protein MOAP-1 (previously referred to as MAP-1). However, the dynamics of death receptor recruitment of RASSF1A and MOAP-1 are still not understood. We have now detailed recruitment to death receptors (tumor necrosis factor receptor 1 [TNF-R1] and TRAIL-R1/DR4) and identified domains of RASSF1A and MOAP-1 that are required for death receptor interaction. Upon TNF-α stimulation, the C-terminal region of MOAP-1 associated with the death domain of TNF-R1; subsequently, RASSF1A was recruited to MOAP-1/TNF-R1 complexes. Prior to recruitment to TNF-R1/MOAP-1 complexes, RASSF1A homodimerization was lost. RASSF1A associated with the TNF-R1/MOAP-1 or TRAIL-R1/MOAP-1 complex via its N-terminal cysteine-rich (C1) domain containing a potential zinc finger binding motif. Importantly, TNF-R1 association domains on both MOAP-1 and RASSF1A were essential for death receptor-dependent apoptosis. The association of RASSF1A and MOAP-1 with death receptors involves an ordered recruitment to receptor complexes to promote cell death and inhibit tumor formation.

scholarly journals TVB Receptors for Cytopathic and Noncytopathic Subgroups of Avian Leukosis Viruses Are Functional Death Receptors

2000 ◽  
Vol 74 (24) ◽  
pp. 11490-11494 ◽  
Author(s):  
Jürgen Brojatsch ◽  
John Naughton ◽  
Heather B. Adkins ◽  
John A. T. Young
Keyword(s):  
Cell Death ◽  
Viral Infections ◽  
Tumor Necrosis Factor Receptor ◽  
Death Receptor ◽  
Death Receptors ◽  
Death Domain ◽  
Cytopathic Effects ◽  
Receptor Interactions ◽  
Surface Envelope

ABSTRACT The identification of TVBS3, a cellular receptor for the cytopathic subgroups B and D of avian leukosis virus (ALV-B and ALV-D), as a tumor necrosis factor receptor-related death receptor with a cytoplasmic death domain, provides a compelling argument that viral Env-receptor interactions are linked to cell death (4). However, other TVB proteins have been described that appear to have similar death domains but are cellular receptors for the noncytopathic subgroup E of ALV (ALV-E): TVBT, a turkey subgroup E-specific ALV receptor, and TVBS1, a chicken receptor for subgroups B, D, and E ALV. To begin to understand the role of TVB receptors in the cytopathic effects associated with infection by specific ALV subgroups, we asked whether binding of a soluble ALV-E surface envelope protein (SU) to its receptor can lead to cell death. Here we report that ALV-E SU-receptor interactions can induce apoptosis in quail or turkey cells. We also show directly that TVBS1and TVBT are functional death receptors that can trigger cell death by apoptosis via a mechanism involving their cytoplasmic death domains and activation of the caspase pathway. These data demonstrate that ALV-B and ALV-E use functional death receptors to enter cells, and it remains to be determined why only subgroups B and D viral infections lead specifically to cell death.

scholarly journals TRUSS, a Novel Tumor Necrosis Factor Receptor 1 Scaffolding Protein That Mediates Activation of the Transcription Factor NF-κB

2003 ◽  
Vol 23 (22) ◽  
pp. 8334-8344 ◽  
Author(s):  
Surinder M. Soond ◽  
Jennifer L. Terry ◽  
Jeff D. Colbert ◽  
David W. H. Riches
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Proximal Region ◽  
Scaffolding Protein ◽  
Death Domain ◽  
Interacting Protein ◽  
Mouse Tissues ◽  
Tnf Α ◽  
Necrosis Factor

ABSTRACT We describe the cloning and characterization of tumor necrosis factor receptor (TNF-R)-associated ubiquitous scaffolding and signaling protein (TRUSS), a novel TNF-R1-interacting protein of 90.7 kDa. TRUSS mRNA was ubiquitously expressed in mouse tissues but was enriched in heart, liver, and testis. Coimmunoprecipitation experiments showed that TRUSS was constitutively associated with unligated TNF-R1 and that the complex was relatively insensitive to stimulation with TNF-α. Deletion mutagenesis of TNF-R1 indicated that TRUSS interacts with both the membrane-proximal region and the death domain of TNF-R1. In addition, the N-terminal region of TRUSS (residues 1 to 440) contains sequences that permit association with the cytoplasmic domain of TNF-R1. Transient overexpression of TRUSS activated NF-κB and increased NF-κB activation in response to ligation of TNF-R1. In contrast, a COOH-terminal-deletion mutant of TRUSS (TRUSS1-723) was found to inhibit NF-κB activation by TNF-α. Coprecipitation and coimmunoprecipitation assays revealed that TRUSS can interact with TRADD, TRAF2, and components of the IKK complex. These findings suggest that TRUSS may serve as a scaffolding protein that interacts with TNF-R1 signaling proteins and may link TNF-R1 to the activation of IKK.

scholarly journals Focal Adhesion Kinase Suppresses Apoptosis by Binding to the Death Domain of Receptor-Interacting Protein

2004 ◽  
Vol 24 (10) ◽  
pp. 4361-4371 ◽  
Author(s):  
Elena Kurenova ◽  
Li-Hui Xu ◽  
Xihui Yang ◽  
Albert S. Baldwin ◽  
Rolf J. Craven ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Tumor Cells ◽  
Focal Adhesion ◽  
Death Receptor ◽  
Human Tumors ◽  
Receptor Complex ◽  
Death Domain ◽  
Functional Link ◽  
Interacting Protein ◽  
Survival Signals

ABSTRACT Tumor cells resist the apoptotic stimuli associated with invasion and metastasis by activating survival signals that suppress apoptosis. Focal adhesion kinase (FAK), a tyrosine kinase that is overexpressed in a variety of human tumors, mediates one of these survival signals. Attenuation of FAK expression in tumor cells results in apoptosis that is mediated by caspase 8- and FADD-dependent pathways, suggesting that death receptor pathways are involved in the process. Here, we report a functional link between FAK and death receptors. We have demonstrated that FAK binds to the death domain kinase receptor-interacting protein (RIP). RIP is a major component of the death receptor complex and has been shown to interact with Fas and tumor necrosis factor receptor 1 through its binding to adapter proteins. We have shown that RIP provides proapoptotic signals that are suppressed by its binding to FAK. We thus propose that FAK overexpression in human tumors provides a survival signal function by binding to RIP and inhibiting its interaction with the death receptor complex.

scholarly journals Sweet modification and regulation of death receptor signalling pathway

2021 ◽  
Author(s):  
Kenta Moriwaki ◽  
Francis K M Chan ◽  
Eiji Miyoshi
Keyword(s):  
Critical Role ◽  
Immune Surveillance ◽  
Death Receptor ◽  
Death Receptors ◽  
Receptor Activation ◽  
Intracellular Signalling ◽  
Human Diseases ◽  
Tumour Necrosis Factor Receptor ◽  
Death Domain ◽  
Receptor Signalling

Abstract Death receptors, members of the tumour necrosis factor receptor (TNFR) superfamily, are characterized by the presence of a death domain in the cytosolic region. TNFR1, Fas and TNF-related apoptosis-inducing ligand receptors, which are prototypical death receptors, exert pleiotropic functions in cell death, inflammation and immune surveillance. Hence, they are involved in several human diseases. The activation of death receptors and downstream intracellular signalling is regulated by various posttranslational modifications, such as phosphorylation, ubiquitination and glycosylation. Glycosylation is one of the most abundant and versatile modifications to proteins and lipids, and it plays a critical role in the development and physiology of organisms, as well as the pathology of many human diseases. Glycans control a number of cellular events, such as receptor activation, signal transduction, endocytosis, cell recognition and cell adhesion. It has been demonstrated that oligo- and monosaccharides modify death receptors and intracellular signalling proteins and regulate their functions. Here, we review the current understanding of glycan modifications of death receptor signalling and their impact on signalling activity.

Death receptors

2003 ◽  
Vol 39 ◽  
pp. 53-71 ◽  
Author(s):  
Harald Wajant
Keyword(s):  
Molecular Mechanisms ◽  
Ectodermal Dysplasia ◽  
Death Receptor ◽  
Growth Factor Receptor ◽  
Death Receptors ◽  
Tnf Receptor ◽  
Death Domain ◽  
Receptor Signalling ◽  
Death Receptor 3 ◽  
Necrosis Factor

Death receptors [Fas/Apo-1/CD95, TNF-R1 [tumour necrosis factor (TNF) receptor 1], DR3 [death receptor 3], TRAIL-R1 [TNF-related apoptosis-inducing ligand receptor 1], TRAIL-R2, DR6, p75-NGFR [p75-nerve growth factor receptor], EDAR [ectodermal dysplasia receptor]] form a subgroup of the TNF-R superfamily that can induce apoptosis (programmed cell death) via a conserved cytoplasmic signalling module termed the death domain. Although death receptors have been recognized mainly as apoptosis inducers, there is growing evidence that these receptors also fulfil a variety of nonapoptotic functions. This review is focused on the molecular mechanisms of apoptotic and non-apoptotic death receptor signalling in light of the phenotype of mice deficient in the various death receptors.

scholarly journals Caspases: the executioners of apoptosis

1997 ◽  
Vol 326 (1) ◽  
pp. 1-16 ◽  
Author(s):  
Gerald M. COHEN
Keyword(s):  
Cell Death ◽  
Morphological Changes ◽  
Cysteine Proteases ◽  
Death Receptors ◽  
Small Subunit ◽  
Caspase 8 ◽  
Death Domain ◽  
Interacting Protein ◽  
Death Effector ◽  
Caspase 2

Apoptosis is a major form of cell death, characterized initially by a series of stereotypic morphological changes. In the nematode Caenorhabditis elegans, the gene ced-3 encodes a protein required for developmental cell death. Since the recognition that CED-3 has sequence identity with the mammalian cysteine protease interleukin-1β-converting enzyme (ICE), a family of at least 10 related cysteine proteases has been identified. These proteins are characterized by almost absolute specificity for aspartic acid in the P1 position. All the caspases (ICE-like proteases) contain a conserved QACXG (where X is R, Q or G) pentapeptide active-site motif. Caspases are synthesized as inactive proenzymes comprising an N-terminal peptide (prodomain) together with one large and one small subunit. The crystal structures of both caspase-1 and caspase-3 show that the active enzyme is a heterotetramer, containing two small and two large subunits. Activation of caspases during apoptosis results in the cleavage of critical cellular substrates, including poly(ADP-ribose) polymerase and lamins, so precipitating the dramatic morphological changes of apoptosis. Apoptosis induced by CD95 (Fas/APO-1) and tumour necrosis factor activates caspase-8 (MACH/FLICE/Mch5), which contains an N-terminus with FADD (Fas-associating protein with death domain)-like death effector domains, so providing a direct link between cell death receptors and the caspases. The importance of caspase prodomains in the regulation of apoptosis is further highlighted by the recognition of adapter molecules, such as RAIDD [receptor-interacting protein (RIP)-associated ICH-1/CED-3-homologous protein with a death domain]/CRADD (caspase and RIP adapter with death domain), which binds to the prodomain of caspase-2 and recruits it to the signalling complex. Cells undergoing apoptosis following triggering of death receptors execute the death programme by activating a hierarchy of caspases, with caspase-8 and possibly caspase-10 being at or near the apex of this apoptotic cascade.

scholarly journals Caspase-8 prevents sustained activation of NF-κB in monocytes undergoing macrophagic differentiation

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1442-1450 ◽  
Author(s):  
Cédric Rébé ◽  
Séverine Cathelin ◽  
Sophie Launay ◽  
Rodolphe Filomenko ◽  
Laurent Prévotat ◽  
...  
Keyword(s):  
Death Receptor ◽  
Adaptor Protein ◽  
Cell Types ◽  
Caspase 8 ◽  
Specific Cell ◽  
Death Domain ◽  
Blood Monocytes ◽  
Inhibitory Protein ◽  
Interacting Protein ◽  
Macrophage Colony

Abstract Caspases have demonstrated several nonapoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral-blood monocytes into macrophages. On macrophage colony-stimulating factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-associated death domain (FADD), the serine/threonine kinase receptor-interacting protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase-8 cleaves RIP1, which prevents sustained NF-κB activation, and activates downstream caspases. Together these data identify a role for caspase-8 in monocytes undergoing macrophagic differentiation, that is, the enzyme activated in an atypical complex down-regulates NF-κB activity through RIP1 cleavage.

scholarly journals Extrinsic or Intrinsic Apoptosis by Curcumin and Light: Still a Mystery

2019 ◽  
Vol 20 (4) ◽  
pp. 905 ◽  
Author(s):  
Vesselina Laubach ◽  
Roland Kaufmann ◽  
August Bernd ◽  
Stefan Kippenberger ◽  
Nadja Zöller
Keyword(s):  
Cell Lines ◽  
Curcuma Longa ◽  
Death Receptor ◽  
Redox Balance ◽  
Death Receptors ◽  
Test System ◽  
Tnf Α ◽  
Epithelial Cell Lines ◽  
Membrane Bound ◽  
Apoptotic Effects

Curcumin—a rhizomal phytochemical from the plant Curcuma longa—is well known to inhibit cell proliferation and to induce apoptosis in a broad range of cell lines. In previous studies we showed that combining low curcumin concentrations and subsequent ultraviolet A radiation (UVA) or VIS irradiation induced anti-proliferative and pro-apoptotic effects. There is still debate whether curcumin induces apoptosis via the extrinsic or the intrinsic pathway. To address this question, we investigated in three epithelial cell lines (HaCaT, A431, A549) whether the death receptors CD95, tumor necrosis factor (TNF)-receptor I and II are involved in apoptosis induced by light and curcumin. Cells were incubated with 0.25–0.5 µg/mL curcumin followed by irradiation with 1 J/cm2 UVA. This treatment was combined with inhibitors specific for distinct membrane-bound death receptors. After 24 h apoptosis induction was monitored by quantitative determination of cytoplasmic histone-associated-DNA-fragments. Validation of our test system showed that apoptosis induced by CH11 and TNF-α could be completely inhibited by their respective antagonists. Interestingly, apoptosis induced by curcumin/light treatment was reversed by none of the herein examined death receptor antagonists. These results indicate a mechanism of action independent from classical death receptors speaking for intrinsic activation of apoptosis. It could be speculated that a shift in cellular redox balance might prompt the pro-apoptotic processes.

scholarly journals Restoration of NF-κB Activation by Tumor Necrosis Factor Alpha Receptor Complex-Targeted MEKK3 in Receptor-Interacting Protein-Deficient Cells

2004 ◽  
Vol 24 (24) ◽  
pp. 10757-10765 ◽  
Author(s):  
Marzenna Blonska ◽  
Yun You ◽  
Romas Geleziunas ◽  
Xin Lin
Keyword(s):  
Tumor Necrosis Factor ◽  
Fusion Protein ◽  
Tumor Necrosis ◽  
Receptor Complex ◽  
Death Domain ◽  
Necrosis Factor Alpha ◽  
Interacting Protein ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor alpha (TNF-α)-induced NF-κB activation. However, the mechanism by which RIP mediates TNF-α-induced signal transduction is not fully understood. In this study, we reconstituted RIP-deficient Jurkat T cells with a fusion protein composed of full-length MEKK3 and the death domain of RIP (MEKK3-DD). In these cells, MEKK3-DD substitutes for RIP and directly associates with TRADD in TNF receptor complexes following TNF-α stimulation. We found that TNF-α-induced NF-κB activation was fully restored by MEKK3-DD in these cells. In contrast, expression of a fusion protein composed of NEMO, a component of the IκB kinase complex, and the death domain of RIP (NEMO-DD) cannot restore TNF-α-induced NF-κB activation in RIP-deficient cells. These results indicate that the role of RIP is to specifically recruit MEKK3 to the TNF-α receptor complex, whereas the forced recruitment of NEMO to the TNF-α receptor complex is insufficient for TNF-α-induced NF-κB activation. Although MEKK2 has a high degree of homology with MEKK3, MEKK2-DD, unlike MEKK3-DD, also fails to restore TNF-α-induced NF-κB activation in RIP-deficient cells, indicating that RIP-dependent recruitment of MEKK3 plays a specific role in TNF-α signaling.

scholarly journals Mitochondrial ROS prime the hyperglycemic shift from apoptosis to necroptosis

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Matthew A. Deragon ◽  
William D. McCaig ◽  
Payal S. Patel ◽  
Robert J. Haluska ◽  
Alexa L. Hodges ◽  
...  
Keyword(s):  
Brain Injury ◽  
Death Receptor ◽  
Interacting Protein ◽  
Mitochondrial Superoxide ◽  
Mitochondrial Ros ◽  
Tnf Α ◽  
Executioner Caspases ◽  
Induced Apoptosis ◽  
Major Factors

AbstractWe have previously identified a shift from TNF-α-induced apoptosis to necroptosis that occurs under hyperglycemic conditions. This shift involves the downregulation or silencing of caspases and concurrent upregulation of necroptotic proteins leading to activation of the necrosome. In addition, under hyperglycemic conditions in vivo, this shift in cell death mechanisms exacerbates neonatal hypoxia-ischemia (HI) brain injury. Here, we identify two major factors that drive the hyperglycemic shift to necroptosis: (1) reactive oxygen species (ROS) and (2) receptor-interacting protein kinase 1 (RIP1). ROS, including mitochondrial superoxide, led to the oxidation of RIP1, as well as formation and activation of the necrosome. Concurrently, ROS mediate a decrease in the levels and activation of executioner caspases-3, -6, and -7. Importantly, hyperglycemia and mitochondrial ROS result in the oxidation of RIP1 and loss of executioner caspases prior to death receptor engagement by TNF-α. Moreover, RIP1 partially controlled levels of mitochondrial ROS in the context of hyperglycemia. As a result of its regulation of ROS, RIP1 also regulated necrosome activation and caspase loss. Mitochondrial ROS exacerbated neonatal HI-brain injury in hyperglycemic mice, as a result of the shift from apoptosis to necroptosis.

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