Selective Activation of NF-κB by Nerve Growth Factor Through the Neurotrophin Receptor p75

Carter, Bruce D.; Kaltschmidt, Christian; Kaltschmidt, Barbara; Offenhäuser, Nina; Bohm-Matthaei, R.; Baeuerle, Patrick A.; Barde, Yves‐Alain

doi:10.1126/science.272.5261.542

Cited by 644 publications

(449 citation statements)

References 35 publications

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“…p75 NTR has been shown to enhance NGF binding and signaling through TrkA (51)(52)(53)(54). p75 NTR also initiates signal transduction separately from TrkA (55)(56)(57). There is increasing evidence that the signals generated by p75 NTR promote programmed cell death (58)(59)(60)(61) rather than prevent it, as does TrkA (62).…”

Section: Resultsmentioning

confidence: 99%

A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA

Grimes

Beattie²,

Mobley³

1997

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

159

138

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The topology of signal transduction is particularly important for neurons. Neurotrophic factors such as nerve growth factor (NGF) interact with receptors at distal axons and a signal is transduced by retrograde transport to the cell body to ensure survival of the neuron. We have discovered an organelle that may account for the retrograde transport of the neurotrophin signal. This organelle is derived from endocytosis of the receptor tyrosine kinase for NGF, TrkA. In vitro reactions containing semi-intact PC12 cells and ATP were used to enhance recovery of a novel organelle: small vesicles containing internalized NGF bound to activated TrkA. These vesicles were distinct from clathrin coated vesicles, uncoated primary endocytic vesicles, and synaptic vesicles, and resembled transport vesicles in their sedimentation velocity. They contained 10% of the total bound NGF and almost one-third of the total tyrosine phosphorylated TrkA. These small vesicles are compelling candidates for the organelles through which the neurotrophin signal is conveyed down the axon.

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Section: Resultsmentioning

confidence: 99%

A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA

Grimes

Beattie²,

Mobley³

1997

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

159

138

View full text Add to dashboard Cite

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“…A growing list of signals that can activate NF-kB in neurons includes tumor necrosis factor-a (TNF), 9 the excitatory neurotransmitter glutamate, 3 nerve growth factor (NGF), 10,11 activity-dependent neurotrophic factor (ADNF), 12 a secreted form of amyloid precursor protein 13 and cell adhesion molecules. 14 These molecules can activate NF-kB through coupling to kinase cascades including calcium/calmodulindependent kinase II, 15 Akt 16,17 and protein kinase C 18 ( Figure 2).…”

Section: The Basics Activation Of Nf-jb In Neuronsmentioning

confidence: 99%

“…Separate activation of either the p75 NTR or trkA is sufficient to lead to NF-kB activation. 10,31 However, interactions in the signaling pathways downstream of either trkA or p75 NTR are likely to have potential impacts on NF-kBdependent regulation of gene expression. In studies using chimeric receptors to isolate the signaling pathways in a neuronal cell line (PC12), Foehr et al found that the p75 NTR activated the p65, p50 and p52 subunits of NF-kB, while trkA activated only p50 and p65.…”

Section: Growth Factor Signalingmentioning

confidence: 99%

Roles for NF-κB in nerve cell survival, plasticity, and disease

2006

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Here we review evidence of roles for NF-jB in the regulation of developmental and synaptic plasticity, and cell survival in physiological and pathological settings. Signaling pathways modulating NF-jB activity include those engaged by neurotrophic factors, neurotransmitters, electrical activity, cytokines, and oxidative stress. Emerging findings support a pivotal role for NF-jB as a mediator of transcription-dependent enduring changes in the structure and function of neuronal circuits. Distinct subunits of NF-jB may uniquely affect cognition and behavior by regulating specific target genes. NF-jB activation can prevent the death of neurons by inducing the production of antiapoptotic proteins such as Bcl-2, IAPs and manganese superoxide dismutase (Mn-SOD). Recent findings indicate that NF-jB plays important roles in disorders such as epilepsy, stroke, Alzheimer's and Parkinson's diseases, as well as oncogenesis. Molecular pathways upstream and downstream of NF-jB in neurons are being elucidated and may provide novel targets for therapeutic intervention in various neurological disorders.

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“…Indeed, it has been reported that NGF binding to p75 NTR stimulate glycosyl-phosphatidylinositol hydrolysis in cochleovestibular ganglia cells (Represa et al, 1991) and induces di erentiation, through the sphingomyelin pathway, in glioma cells that lack TrkA (Dobrowsky et al, 1994). Furthermore, activation of the transcription factor NF-kB by NGF, but not BDNF or NT-3 through p75 NTR has been reported in Schwann cells (Carter et al, 1996). These ®ndings clearly demonstrate the existence of di erent signal transduction pathways speci®cally coupled to p75 NTR , independent of TrkA.…”

Section: Bep75bmentioning

confidence: 99%

Induction of apoptosis by p75 neurotrophin receptor in human neuroblastoma cells

et al. 1997

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The low-a nity nerve growth factor receptor p75 NTR belongs to a membrane receptor superfamily whose members, in certain cell types, are able to transduce an apoptotic signal. To investigate the e ect of p75 NTR expression in neuroblastoma cells, we transfected the p75 NTR cDNA into SK-N-BE cells, a neuroblastoma cell line that lacks expression of both p75 NTR and TrkA. Cell clones expressing elevated levels of p75 NTR showed a high degree of cell death by apoptosis, even in serumsupplemented medium. Moreover, the level of apoptosis correlated directly with the expression level of the receptor, indicating that p75 NTR could activate the cell death program by itself. Clones expressing p75 NTR showed a dramatic increase of cell death when switched into serum-free medium; these cultures rapidly extinguished. This apoptotic e ect was greatly inhibited by NGF treatment. Our results support the hypothesis that p75 NTR , when it is not bound by NGF, may play a role in neuronal selection during embryonic development and suggest that neuroblastomas may arise from immature neuroblasts that escape programmed cell death. Therefore, the loss of p75 NTR expression in developing neural crest cells might be a primary event in the genesis of neuroblastoma.

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Selective Activation of NF-κB by Nerve Growth Factor Through the Neurotrophin Receptor p75

Cited by 644 publications

References 35 publications

A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA

A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA

Roles for NF-κB in nerve cell survival, plasticity, and disease

Induction of apoptosis by p75 neurotrophin receptor in human neuroblastoma cells

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