Association of the p75 Neurotrophin Receptor with TRAF6

Khursigara, Gus; Orlinick, Jason R.; Chao, Moses V.

doi:10.1074/jbc.274.5.2597

Cited by 222 publications

(202 citation statements)

References 41 publications

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“…We expected the resulting construct to compete effectively for binding to NGF against the endogenous p75 but be incapable of its own signaling. To facilitate the detection of the chimeric receptor, an HA tag was placed at the N terminus of rat p75 cDNA after the signal peptide sequence (Khursigara et al, 1999). Because the adenovirus contains GFP under a separate promoter (Fig.…”

Section: Results P75 Protein Is Required For Ngf-dependent Apoptosis mentioning

confidence: 99%

Activation of Rac GTPase by p75 Is Necessary for c-junN-Terminal Kinase-Mediated Apoptosis

Harrington

Kim

Yoon³

2002

J. Neurosci.

188

168

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The neurotrophin receptor p75 can induce apoptosis both in vitro and in vivo. The mechanisms by which p75 induces apoptosis have remained mostly unknown. Here, we report that p75 activates Rac GTPase, which in turn activates c-jun N-terminal kinase (JNK), including an injury-specific JNK3, in an NGF-dependent manner. N17Rac blocks this JNK activation and subsequent NGF-dependent apoptosis, indicating that activation of Rac GTPase is required for JNK activation and apoptosis induced by p75. In addition, p75-mediated Rac activation is modulated by coactivation of Trk, identifying Rac GTPase as one of the key molecules whose activity is critical for cell survival and death in neurotrophin signaling. The crucial role of the JNK pathway in p75 signaling is further confirmed by the results that blocking p75 from signaling via the JNK pathway or suppressing the JNK activity itself led to inhibition of NGF-dependent death. Together, these results indicate that the apoptotic machinery of p75 comprises Rac GTPase and JNK.

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Section: Results P75 Protein Is Required For Ngf-dependent Apoptosis mentioning

confidence: 99%

Activation of Rac GTPase by p75 Is Necessary for c-junN-Terminal Kinase-Mediated Apoptosis

Harrington

Kim

Yoon³

2002

J. Neurosci.

188

168

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“…72 The presence of TRAF2 or TRAF6 proteins in the cytoplasm of motor neurons sequesters the death receptors, aiding in survival of the neuron. 73,74 However, E2F-1 located in the cytoplasm may induce complex formation with TRAF proteins to impede their function, thus releasing death receptors that could now induce cell death via the p75 NTR pathway or other death receptor pathways. [72][73][74] There is indeed precedence to the interactions of E2F-1 with the TRAF proteins in other cell types.…”

Section: Discussionmentioning

confidence: 99%

“…73,74 However, E2F-1 located in the cytoplasm may induce complex formation with TRAF proteins to impede their function, thus releasing death receptors that could now induce cell death via the p75 NTR pathway or other death receptor pathways. [72][73][74] There is indeed precedence to the interactions of E2F-1 with the TRAF proteins in other cell types. 72 This hypothesis warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis

Ranganathan

Bowser

2003

The American Journal of Pathology

152

111

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Amyotrophic lateral sclerosis (ALS) is characterizedby progressive degeneration of the motor neurons in the cerebral cortex, brain stem, and spinal cord. However, the mechanisms that regulate the initiation and/or progression of motor neuron loss in this disease remain enigmatic. Cell-cycle proteins and transcriptional regulators such as cyclins, cyclin-associated kinases, the retinoblastoma gene product (pRb), and E2F-1 function during cellular proliferation, differentiation, and cell death pathways. Recent data has implicated increased expression and activation of various cell-cycle proteins in neuronal cell death. We have examined the expression and subcellular distribution of G 1 to S phase cell-cycle regulators in the spinal cord, motor cortex, and sensory cortex from clinically and neuropathologically diagnosed sporadic ALS cases and age-matched controls. Our results indicate hyperphosphorylation of the retinoblastoma protein in motor neurons during ALS, concurrent with increased levels of cyclin D, and redistribution of E2F-1 into the cytoplasm of motor neurons and glia. These data suggest that G 1 to S phase activation occurs during ALS and may participate in molecular mechanisms regulating motor neuron death. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease exemplified by neuronal loss in the motor cortex, brainstem, and spinal cord ventral horn. This progressive neurodegeneration results in muscle atrophy, paralysis, and death. Disease onset may occur at any age but is most common between 40 to 70 years of age. The average time interval from diagnosis to mortality is ϳ4 years. 1,2 Familial ALS comprises a fraction (5 to 10%) of ALS cases and is predominantly inherited in an autosomal dominant manner and includes mutations in the SOD1 and the ALS2 genes. [3][4][5][6][7] The etiology of ALS is thought to be multifactorial. Factors believed to participate in motor neuron degeneration include glutamate-mediated excitotoxicity, free radical accumulation because of oxidative stress, increased intracellular calcium, mitochondrial dysfunction, cytoskeletal abnormalities, astrogliosis, and genetic mutations. 8 -13 Neuronal dysfunction because of retrograde degeneration of the presynaptic axons may occur as the result of insufficient release of activity-dependent target-derived neurotrophic factors. 14 One important consequence of inappropriate trophic factor support is altered intracellular signaling to the nucleus. Signaling from the cell surface to the nucleus modulates chromatin structure and the activity of transcription factors, resulting in altered gene transcription. One potential mechanism leading to neuronal death in ALS includes altered expression of pro-and anti-apoptotic genes. 15 Another potential cell death mechanism is the inappropriate expression or activation of cell-cycle proteins. 16 The cell cycle is associated with the phasespecific expression or modification of defined sets of cell-cycle regulatory genes that regulate cellular proliferation, differentiation or entry into...

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“…32 Research in the past few years has revealed that the p75 NTR is coupled to both JNK and NF-kB activation through the tumor necrosis factor receptorassociated factor-6 (TRAF6) protein. 33 TRAF6 is one of the six TRAF family members identified to date and is expressed in most tissues, including the CNS. A dominant negative mutant of TRAF6 effectively inhibits NF-kB activation through the p75 NTR , while not affecting activation through trkA.…”

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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Association of the p75 Neurotrophin Receptor with TRAF6

Cited by 222 publications

References 41 publications

Activation of Rac GTPase by p75 Is Necessary for c-junN-Terminal Kinase-Mediated Apoptosis

Activation of Rac GTPase by p75 Is Necessary for c-junN-Terminal Kinase-Mediated Apoptosis

Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis

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

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