A comparison of the cytoplasmic domains of the Fas receptor and the p75 neurotrophin receptor

Kong, Hyesik; Kim, A. H.; Orlinick, Jason R.; Chao, Moses V.

doi:10.1038/sj.cdd.4400587

Cited by 39 publications

(27 citation statements)

References 40 publications

(42 reference statements)

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“…Similar to E8, FADD DN inhibits recruitment of both caspase 8 and caspase 10 to the DISC (57). The involvement of different apical caspases and adaptor proteins is furthermore indicated by the observation that a fusion protein between the extracellular domain of Fas and the intracellular domain of p75 NTR is not able to kill cells that readily die by expression of Fas (58). Nonetheless, the E8 results indicate that death effector domain interactions are essential for p75 NTR signaling, much as they are needed for signaling from the other DRs.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a p75NTR Apoptotic Signaling Pathway Using a Novel Cellular Model

Wang¹,

Bauer²,

Li³

et al. 2001

Journal of Biological Chemistry

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The p75 neurotrophin receptor (p75 NTR ) belongs to the tumor necrosis factor receptor/nerve growth factor receptor superfamily. In some cells derived from neuronal tissues it causes cell death through a poorly characterized pathway. We developed a neuronal system using conditionally immortalized striatal neurons, in which the expression of p75 NTR is inducibly controlled by the ecdysone receptor. In these cells p75 NTR induces apoptosis through its death domain in a nerve growth factor-independent manner. Caspases 9, 6, and 3 are activated by receptor expression indicating the activation of the common effector pathway of apoptosis. Cell death is blocked by a dominant negative form of caspase 9 and Bcl-X L consistent with a pathway that involves mitochondria. Significantly, the viral flice inhibitory protein E8 protects from p75 NTR -induced cell death indicating that death effector domains are involved. A p75 NTR construct with a deleted death domain dominantly interferes with p75 NTR signaling, implying that receptor multimerization is required. However, in contrast to the other receptors of the family, p75 NTR -mediated apoptosis does not involve the adaptor proteins Fas-associated death domain protein or tumor necrosis factor-associated death domain protein, and the apical caspase 8 is not activated. We conclude that p75 NTR signals apoptosis by similar mechanisms as other death receptors but uses different adaptors and apical caspases.

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Section: Discussionmentioning

confidence: 99%

Characterization of a p75NTR Apoptotic Signaling Pathway Using a Novel Cellular Model

Wang¹,

Bauer²,

Li³

et al. 2001

Journal of Biological Chemistry

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“…75,78,79 However, despite this apparent functional similarity to Fas and TNFR I, and the similarities in structure of these three proteins, Fas-p75NTR chimeras consisting of the extracellular domain of Fas and the intracellular domain of p75NTR failed to induce apoptosis. 92 Thus, apoptosis induction following NGF binding to p75 NTR is somehow different from following the binding of death factors to Fas and TNFR I. This may be a Trk-dependent phenomenon, since it has been described almost exclusively in systems in which mismatched Trk members (e.g., Trk B with NGF or Trk A with BDNF) have been expressed.…”

Section: Patched: Hedging Bets On Neural Tube Developmentmentioning

confidence: 99%

Receptors that mediate cellular dependence

2005

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Cells depend for their survival on stimulation by trophic factors and other prosurvival signals, the withdrawal of which induces apoptosis, both via the loss of antiapoptotic signaling and the activation of proapoptotic signaling via specific receptors. These receptors, dubbed dependence receptors, activate apoptotic pathways following the withdrawal of trophic factors and other supportive stimuli. Such receptors may feature in developmental cell death, carcinogenesis (including metastasis), neurodegeneration, and possibly subapoptotic events such as neurite retraction and somal atrophy. Mechanistic studies of dependence receptors suggest that these receptors form ligand-dependent complexes that include specific caspases. Complex formation in the absence of ligand leads to caspase activation by a mechanism that is typically dependent on caspase cleavage of the receptor itself, releasing proapoptotic peptides. Cellular dependence receptors, considered in the aggregate, may thus form a system of molecular integration, analogous to the electrical integration system provided by dendritic arbors in the nervous system.

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“…Unlike the Trk receptors that possess signature tyrosine kinase motifs, p75 NTR lacks any intrinsic catalytic activity. The p75 NTR receptor mediates signals through a series of adaptor proteins (1,6,8,17). The role of p75 NTR in cell signaling, particularly apoptosis, is being found to be increasingly important.…”

mentioning

confidence: 99%

Construction of a mutated pro-nerve growth factor resistant to degradation and suitable for biophysical and cellular utilization

Pagadala

Dvorak

Neet

2006

Proc. Natl. Acad. Sci. U.S.A.

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Precursor of nerve growth factor (proNGF) has been found to be proapoptotic in several cell types and mediates its effects by binding to p75 neurotrophin receptor (p75 NTR ) and sortilin. The proNGF molecule is processed by proteases at three dibasic sites found in the pro domain to form mature NGF (termed herein as sites 1, 2, and 3 from the proNGF N terminus). Of these processing sites, site 3, adjacent to the N terminus of mature NGF, was thought to be the major site responsible for processing of proNGF to mature NGF. We found that mutating this major processing site (site 3) resulted in a form of proNGF that was only partially stable. On introducing additional mutations in the pro domain at the other two dibasic sites, we found the stability of proNGF to increase significantly. Here we describe the construction, expression, and purification of this more stable proNGF molecule. The two consecutive basic residues at each of the three sites were mutated to neutral alanine residues. Expression was performed in stably transfected Sf21 insect cells. Purification involved strong cationexchange chromatography and N60 immunoaffinity column chromatography. The construct with all three sites mutated (termed proNGF123) gave all proNGF with no mature NGF and was not cleaved by three proconvertases (furin, PACE-4, and PC-2) known to proteolyze proneurotrophins in vivo. This stable proNGF molecule demonstrated proapoptotic activity on rat pheocytochroma PC12 cells, PC12nnr cells, C6 glioblastoma cells, and RN22 schwannoma cells.p75 receptor ͉ Sf21 stable cell line ͉ Trk receptor ͉ neurotrophin ͉ apoptosis

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A comparison of the cytoplasmic domains of the Fas receptor and the p75 neurotrophin receptor

Cited by 39 publications

References 40 publications

Characterization of a p75NTR Apoptotic Signaling Pathway Using a Novel Cellular Model

Characterization of a p75NTR Apoptotic Signaling Pathway Using a Novel Cellular Model

Receptors that mediate cellular dependence

Construction of a mutated pro-nerve growth factor resistant to degradation and suitable for biophysical and cellular utilization

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