Biogenesis and Function of the NGF/TrkA Signaling Endosome

Marlin, M. Caleb; Li, Guangpu

doi:10.1016/bs.ircmb.2014.10.002

Cited by 114 publications

(85 citation statements)

References 88 publications

(110 reference statements)

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“…These endosomal platforms allow for NGF-TrkA to meet local signaling needs within neuronal extensions and affect gene tran-scription once the endosomes reach the nucleus in the cell body (51). We found that the Ca 2ϩ -permeable protein TRPV2 displays a punctate staining pattern in the extensions of embryonic DRG neurons.…”

Section: Discussionmentioning

confidence: 76%

Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons

Cohen

Johnson

Pilat

et al. 2015

Molecular and Cellular Biology

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Neurite outgrowth is key to the formation of functional circuits during neuronal development. Neurotrophins, including nerve growth factor (NGF), increase neurite outgrowth in part by altering the function and expression of Ca 2؉ -permeable cation channels. Here we report that transient receptor potential vanilloid 2 (TRPV2) is an intracellular Ca 2؉ -permeable TRPV channel upregulated by NGF via the mitogen-activated protein kinase (MAPK) signaling pathway to augment neurite outgrowth. TRPV2 colocalized with Rab7, a late endosome protein, in addition to TrkA and activated extracellular signal-regulated kinase (ERK) in neurites, indicating that the channel is closely associated with signaling endosomes. In line with these results, we showed that TRPV2 acts as an ERK substrate and identified the motifs necessary for phosphorylation of TRPV2 by ERK. Furthermore, neurite length, TRPV2 expression, and TRPV2-mediated Ca 2؉ signals were reduced by mutagenesis of these key ERK phosphorylation sites. Based on these findings, we identified a previously uncharacterized mechanism by which ERK controls TRPV2-mediated Ca 2؉ signals in developing neurons and further establish TRPV2 as a critical intracellular ion channel in neuronal function.E stablishment of precise neural connections during nervous system development is essential in forming functional circuits. Neurite outgrowth allows for connection and communication between developing neurons and their targets. In the developing peripheral nervous system, nerve growth factor (NGF) is a targetderived extracellular cue necessary for outgrowth (1). Upon binding to its extracellular receptor, NGF activates the phosphoinositide 3-kinase (PI3K) signaling pathway, which is essential for the survival of developing neurons, and the mitogen-activated protein kinase (MAPK) pathway, which promotes differentiation and neurite outgrowth (2, 3). These signaling pathways have numerous downstream effectors in developing neurons, including several Ca 2ϩ -permeable transient receptor potential (TRP) channels (4-8).Thermosensitive TRP channels from the vanilloid subfamily (thermoTRPV channels) consist of four nonselective Ca 2ϩ -permeable cation channels, TRP vanilloid 1 (TRPV1) to TRPV4, originally described as pain and temperature sensors in adult sensory neurons (9-12). Recent evidence suggests, however, that only TRPV1 functions as a molecular sensor of heat and painful stimuli in vivo, while the function of TRPV2 to -4 remains unclear (13-16). TRPV2 and TRPV4 have also been detected in developing peripheral neurons, suggesting that they may play a role in growth programs during development (17, 18). Consistent with this notion, TRPV2 has been implicated in axon outgrowth (18), and critical mutations in TRPV4 result in peripheral axonal neuropathies (19,20). Despite these initial findings, the details by which thermoTRPV channels influence neuronal development remain unknown.Here we explore the molecular mechanisms by which thermoTRPV channels contribute to neurotrophin-mediated peripher...

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Section: Discussionmentioning

confidence: 76%

Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons

Cohen

Johnson

Pilat

et al. 2015

Molecular and Cellular Biology

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“…Both distal and central terminals of nociceptive neurons might be altered by peripheral NGF, respectively, through the acute hyper-responsiveness at the periphery and the slow transport of a TrkA-NGF complex to the DRG (Grimes et al, 1996), where changes in receptor synthesis and excitability also occur (Marlin and Li, 2015), as well as by regulation of neuropeptides that enhance pain perception and are secreted at both ends of the neuron (Skoff and Adler, 2006). The combined evidence suggests that PKMζ activity in both the periphery and the spinal cord contributes to thermal and mechanical hyperalgesia, although the pathways for activation may differ between these two modalities (Ostubo et al, 2012), and between peripheral and central loci (see Lewin et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

The TrkA receptor mediates experimental thermal hyperalgesia produced by nerve growth factor: Modulation by the p75 neurotrophin receptor

2017

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The p75 neurotrophin receptor (p75NTR) and its activation of the sphingomyelin signaling cascade are essential for mechanical hypersensitivity resulting from locally injected nerve growth factor (NGF). Here the role of the same effectors, and of the TrkA receptor, are evaluated for thermal hyperalgesia from NGF. Sensitivity of rat hind paw plantar skin to thermal stimulation after local sub-cutaneous injection of NGF (500 ng) was measured by the latency for paw withdrawal (PWL) from a radiant heat source. PWL was reduced from baseline values at 0.5–22h by ~40% from that in naïve or vehicle-injected rats, and recovered to pre-injection levels by 48h. Local pre-injection with a p75NTR blocking antibody did not affect the acute thermal hyperalgesia (0.5–3.5h) but hastened its recovery so that it had reversed to baseline by 22h. In addition, GW4869 (2 mM), an inhibitor of the neutral sphingomyelinase (nSMase) that is an enzyme in the p75NTR pathway, also failed to prevent thermal hyperalgesia. However, C2-ceramide, an analogue of the ceramide produced by sphingomyelinase, did cause thermal hyperalgesia. Injection of an anti-TrkA antibody known to promote dimerization and activation of that receptor, independent of NGF, also caused thermal hyperalgesia, and prevented the further reduction of PWL from subsequently injected NGF. A nonspecific inhibitor of tropomyosin receptor kinases, K252a, prevented thermal hyperalgesia from NGF, but not that from the anti-TrkA antibody. These findings suggest that the TrkA receptor has a predominant role in thermal hypersensitivity induced by NGF, while p75NTR and its pathway intermediates serve a modulatory role.

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“…Receptor signaling from endosomal membranes after endocytosis influences temporal and spatial regulation of signaling effector pathways downstream from receptor activation (Bergeron et al, 2016;Irannejad et al, 2015). The presence of activated FYN in the lumen of MVBs, together with its role in neuronal differentiation noted above, suggests that FYN is potentially another important component of signaling endosomes in neurons, which play an important role in nervous system development and neurodegenerative disease (Bergeron et al, 2016;Chen and Mobley, 2019;Cosker and Segal, 2014;Harrington and Ginty, 2013;Marlin and Li, 2015;Scott-Solomon and Kuruvilla, 2018). Signaling endosomes containing NGF and TRKA have been identified in neurons to be Rab7 positive MVBs (Von Bartheld and Altick, 2011;Harrington and Ginty, 2013).…”

Section: Sequestration Into Mvbs May Simply Lead To Protein Degradatimentioning

confidence: 98%

PAG1 directs SRC-family kinase intracellular localization to mediate receptor tyrosine kinase-induced differentiation

Foltz

Palacios‐Moreno

Mayfield

et al. 2020

Preprint

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All receptor tyrosine kinases (RTKs) activate similar downstream signaling pathways through a common set of effectors, yet it is not fully understood how different receptors elicit distinct cellular responses to cause cell proliferation, differentiation, or other cell fates. We tested the hypothesis that regulation of SRC Family Kinase (SFK) signaling by the scaffold protein, PAG1, influences cell fate decisions following RTK activation.We generated a neuroblastoma cell line expressing a PAG1 fragment that lacks the membrane spanning domain (PAG1 TM-) and localized to the cytoplasm. PAG1 TMcells exhibited higher amounts of active SFKs and increased growth rate. PAG1 TMcells were unresponsive to TRKA and RET signaling, two RTKs that induce neuronal differentiation, but retained responses to EGFR and KIT. Under differentiation conditions, PAG1 TMcells continued to proliferate and did not extend neurites or increase b-III tubulin expression. FYN and LYN were sequestered in multivesicular bodies (MVBs), and dramatically more FYN and LYN were in the lumen of MVBs in PAG1 TMcells. In particular, activated FYN was sequestered in PAG1 TMcells, suggesting that disruption of FYN localization led to the observed defects in differentiation. The results demonstrate that PAG1 directs SFK intracellular localization to control activity and to mediate signaling by RTKs that induce neuronal differentiation.

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Biogenesis and Function of the NGF/TrkA Signaling Endosome

Cited by 114 publications

References 88 publications

Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons

Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons

The TrkA receptor mediates experimental thermal hyperalgesia produced by nerve growth factor: Modulation by the p75 neurotrophin receptor

PAG1 directs SRC-family kinase intracellular localization to mediate receptor tyrosine kinase-induced differentiation

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