A Functional Interaction between the p75 Neurotrophin Receptor Interacting Factors, TRAF6 and NRIF

Gentry, Jennifer J.; Rutkoski, Nancy J.; Burke, Terrence R.; Carter, Bruce D.

doi:10.1074/jbc.m309209200

Cited by 41 publications

(44 citation statements)

References 53 publications

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“…Thus, the structure of NRIF suggests that it regulates gene transcription, which was further supported by evidence that ectopic expression in 293 HEK cells results in a significant portion of NRIF being localized to the nucleus (16,24). However, the results presented here indicate that NRIF functions in mediating p75 activation of JNK, which is required for the receptor to induce cell death.…”

Section: Discussioncontrasting

confidence: 37%

“…5D). Thus, NRIF is necessary, but not sufficient for stimulating the kinase, as was previously suggested based on ectopic expression of NRIF in 293 HEK cells (24).…”

Section: Deletion Of Nrif Does Not Alter the Ability Of P75 To Activatementioning

confidence: 55%

“…TRAF6 also transduces the signal to NF-B and JNK for several other receptors, such as IL-1␤, RANK, and CD40, through a mechanism involving its oli- gomerization (37). Interestingly, NRIF was shown to bind to TRAF6, and the interaction of these two proteins enhanced TRAF6 activation of JNK (24). Moreover, co-expression of NRIF, TRAF6, and p75 in 293 HEK cells reconstituted the ability of NGF to stimulate JNK, whereas neither intracellular protein alone was sufficient (24).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, NRIF was shown to bind to TRAF6, and the interaction of these two proteins enhanced TRAF6 activation of JNK (24). Moreover, co-expression of NRIF, TRAF6, and p75 in 293 HEK cells reconstituted the ability of NGF to stimulate JNK, whereas neither intracellular protein alone was sufficient (24). It was suggested that NRIF FIG.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of JNK activation by p75 has not been delineated; however, TRAF6, a member of the tumor necrosis factor receptor associated factor family (25), and the GTPbinding protein Rac (10) have been implicated as upstream activators. Furthermore, it was recently reported that co-expression of NRIF, TRAF6, and p75 in 293 HEK cells reconstituted JNK activation by neurotrophin (24). Therefore, we evaluated the stimulation of this kinase in neurons from mice lacking nrif.…”

Section: Nrif Is Required For Apoptosis Mediated By the P75mentioning

confidence: 99%

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Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

Linggi

Burke

Williams

et al. 2005

Journal of Biological Chemistry

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Activation of the p75 neurotrophin receptor leads to a variety of effects within the nervous system, including neuronal apoptosis. Both c-Jun N-terminal kinase (JNK) and the tumor suppressor p53 have been reported to be critical for this receptor to induce cell death; however, the mechanisms by which p75 activates these pathways is undetermined. Here we report that the neurotrophin receptor interacting factor (NRIF) is necessary for p75-dependent JNK activation and apoptosis. Upon nerve growth factor withdrawal, nrif؊/؊ sympathetic neurons underwent apoptosis, whereas p75-mediated death was completely abrogated. The lack of cell death correlated with a lack of JNK activation in the nrif؊/؊ neurons, suggesting that NRIF is a selective mediator for p75-dependent JNK activation and apoptosis. Moreover, we document that NRIF expression is sufficient to induce cell death through a mechanism that requires p53. Taken together, these results establish NRIF as an essential component of the p75 apoptotic pathway.The p75 neurotrophin receptor is a pleiotropic signaling molecule that regulates cellular survival, neurite outgrowth, and myelin formation (1). This founding member of the tumor necrosis factor receptor superfamily can directly bind all of the neurotrophins, including nerve growth factor (NGF), 1 brainderived neurotrophic factor (BDNF), and neurotrophin-3 and -4 (NT-3, NT-4), but it also functions as a co-receptor in a variety of protein complexes. p75 can interact with TrkA to form a high affinity neurotrophin binding site (2) and enhance survival signaling (3). It can also associate with the Nogo receptor and Lingo-1 and, upon interaction with myelin proteins, block neurite outgrowth (4, 5), and, together with Sortilin, the neurotensin 3 receptor, it binds the proform of NGF and initiates apoptosis (6). The divergent cellular responses depend on the receptor complex as well as the cellular context. For example, sympathetic neurons of superior cervical ganglia undergo a period of programmed cell death during ontogenesis, and NGF, supplied by the tissues innervated, prevents the loss of these neurons through binding to a p75-TrkA complex (7). In contrast, specific activation of p75 (8) or a p75-sortilin complex (6) induces apoptosis in the neurons. Genetic deletion of p75 prevents the normal period of cell death in the developing superior cervical ganglia (8, 9), thus demonstrating the key role of this receptor in regulating the survival of this neuronal population.How p75 initiates this variety of biological effects is not well understood; however, the stress kinase c-Jun N-terminal kinase, JNK, has been suggested to play a role in mediating this apoptotic signal. Neurotrophin activation of JNK through p75 correlates with the induction of cell death (43) and inhibition of the kinase prevents the receptor from killing (23, 10). Interestingly, c-Jun, the downstream target of the kinase, is not required for the receptor to activate apoptosis (11); however, other JNK substrates have been implicated in the p75 death ...

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Section: Discussioncontrasting

confidence: 37%

“…5D). Thus, NRIF is necessary, but not sufficient for stimulating the kinase, as was previously suggested based on ectopic expression of NRIF in 293 HEK cells (24).…”

Section: Deletion Of Nrif Does Not Alter the Ability Of P75 To Activatementioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Nrif Is Required For Apoptosis Mediated By the P75mentioning

confidence: 99%

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Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

Linggi

Burke

Williams

et al. 2005

Journal of Biological Chemistry

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Interaction of IFNλR1 with TRAF6 regulates NF‐κB activation and IFNλR1 stability

Xie

Cui

Hui

et al. 2012

J of Cellular Biochemistry

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IFNλR1 is a member of the class II cytokine receptor family, and it associates with IL-10R2 to form a functional receptor complex, IFNλR. This receptor complex transduces signals from IFNλs (IFNλ1, IFNλ2, and IFNλ3), promoting antiviral and antiproliferative activities similar to those of type I IFNs. In an effort to further understand signal transduction through IFNλR1, we used bioinformatics analysis and identified a tumor necrosis factor receptor-associated factor 6 (TRAF6)-binding motif in the intracellular domain of IFNλR1. In subsequent immunoprecipitation and GST pull-down assays, IFNλR1 was shown to immunoprecipitate with TRAF6 and was pulled down by GST-TRAF6. Endogenous IFNλR1 and TRAF-6 interaction implies that these proteins really interact in the cells. This interaction was abrogated upon mutation of the TRAF6-binding motif in IFNλR1. Furthermore, the interaction between IFNλR1 and TRAF6 inhibited TRAF6-induced NF-κB activation, likely due to a reduction in TRAF6 autoubiquitination. Moreover, co-expression of IFNλR1 with TRAF6 significantly increased the stability of IFNλR1, thereby prolonging its half-life and enhancing its steady-state level in cultured cells.

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NGF/P75 in Cell Cycle and Tetraploidy

López-Sánchez¹,

Ovejero‐Benito²,

Rodríguez-Ruiz³

et al. 2014

Handbook of Neurotoxicity

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A Functional Interaction between the p75 Neurotrophin Receptor Interacting Factors, TRAF6 and NRIF

Cited by 41 publications

References 53 publications

Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

Interaction of IFNλR1 with TRAF6 regulates NF‐κB activation and IFNλR1 stability

NGF/P75 in Cell Cycle and Tetraploidy

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