High-affinity TrkA and p75 neurotrophin receptor complexes: A twisted affair

Conroy, Jacinta; Coulson, Elizabeth J.

doi:10.1016/j.jbc.2022.101568

Cited by 38 publications

(22 citation statements)

References 139 publications

(221 reference statements)

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“…P75 NTR has long been described as enhancing the action of neurotophins and NGF on their receptors, such as TrkA. In a recent review, Conroy and Coulson elegantly describe the complexity of the interaction between TrkA and p75 NTR from a model of ligand passing model switching to the current theory of allosteric regulation of TrkA by p75 NTR [ 14 ]. It is also known that, under NGF stimulation, p75 NTR can act through its own signaling pathways and notably in the mediation of pain [ 15 ].…”

Section: State Of the Art: Therapeutic Potential Of The Ngf/trka Axismentioning

confidence: 99%

“…The formation of the P75 NTR /TrkA heterodimer (stoichiometry 1:2:1) induces a 100-fold increase in NGF affinity for TrkA [ 35 , 36 ]. As we have previously described, two mechanisms have been proposed to explain how P75 NTR increases NGF affinity for TrkA via its extracellular domain [ 14 ]. The most likely model is the ligand passing model: P75 NTR presents NGF to TrkA and thus does not interact directly with TrkA.…”

Section: Genomic Alterations Cannot Recapitulate All Resistance Mecha...mentioning

confidence: 99%

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TrkA Co-Receptors: The Janus Face of TrkA?

Trouvilliez

Lagadec

Toillon

2023

Cancers

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Larotrectinib and Entrectinib are specific pan-Trk tyrosine kinase inhibitors (TKIs) approved by the Food and Drug Administration (FDA) in 2018 for cancers with an NTRK fusion. Despite initial enthusiasm for these compounds, the French agency (HAS) recently reported their lack of efficacy. In addition, primary and secondary resistance to these TKIs has been observed in the absence of other mutations in cancers with an NTRK fusion. Furthermore, when TrkA is overexpressed, it promotes ligand-independent activation, bypassing the TKI. All of these clinical and experimental observations show that genetics does not explain all therapeutic failures. It is therefore necessary to explore new hypotheses to explain these failures. This review summarizes the current status of therapeutic strategies with TrkA inhibitors, focusing on the mechanisms potentially involved in these failures and more specifically on the role of TrkA.

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Section: State Of the Art: Therapeutic Potential Of The Ngf/trka Axismentioning

confidence: 99%

Section: Genomic Alterations Cannot Recapitulate All Resistance Mecha...mentioning

confidence: 99%

TrkA Co-Receptors: The Janus Face of TrkA?

Trouvilliez

Lagadec

Toillon

2023

Cancers

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“…On the contrary, in the absence of TrkA or in association to sortilin, activation of p75 NTR by proNGF mediates pro-apoptotic signaling in development and/or in neurodegenerative conditions [ 142 , 143 ]. It has been also demonstrated that, in particular conditions, proNGF can bind trkA and p75 NTR , giving rise to a pro-survival outcome [ 116 , 122 , 144 ].…”

Section: Ngf and Alzheimer’s Diseasementioning

confidence: 99%

Targeting the Cation-Chloride Co-Transporter NKCC1 to Re-Establish GABAergic Inhibition and an Appropriate Excitatory/Inhibitory Balance in Selective Neuronal Circuits: A Novel Approach for the Treatment of Alzheimer’s Disease

et al. 2022

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GABA, the main inhibitory neurotransmitter in the adult brain, depolarizes and excites immature neurons because of an initially higher intracellular chloride concentration [Cl−]i due to the delayed expression of the chloride exporter KCC2 at birth. Depolarization-induced calcium rise via NMDA receptors and voltage-dependent calcium channels is instrumental in shaping neuronal circuits and in controlling the excitatory (E)/inhibitory (I) balance in selective brain areas. An E/I imbalance accounts for cognitive impairment observed in several neuropsychiatric disorders. The aim of this review is to summarize recent data on the mechanisms by which alterations of GABAergic signaling alter the E/I balance in cortical and hippocampal neurons in Alzheimer’s disease (AD) and the role of cation-chloride co-transporters in this process. In particular, we discuss the NGF and AD relationship and how mice engineered to express recombinant neutralizing anti-NGF antibodies (AD11 mice), which develop a neurodegenerative pathology reminiscent of that observed in AD patients, exhibit a depolarizing action of GABA due to KCC2 impairment. Treating AD and other forms of dementia with bumetanide, a selective KCC2 antagonist, contributes to re-establishing a proper E/I balance in selective brain areas, leading to amelioration of AD symptoms and the slowing down of disease progression.

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“…The neurotrophin protein family (NTs) is a subgroup of secreted neurotrophic factors that are essential for axonal outgrowth, neuronal differentiation, synaptic plasticity, and neuronal survival [9,28,29]. It comprises Brainderived neurotrophic factor (BDNF), Nerve growth factor (NGF), Neurotrophin 3 (NT3), and Neurotrophin 4 (NT4); proteins that are expressed across the CNS in a spatiotemporal manner.…”

Section: Ad As Imbalance Between Neurodegeneration and Neuroprotectionmentioning

confidence: 99%

Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer’s disease

Salašová

Monti

Andersen

et al. 2022

Mol Neurodegeneration

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The family of VPS10p-Domain (D) receptors comprises five members named SorLA, Sortilin, SorCS1, SorCS2 and SorCS3. While their physiological roles remain incompletely resolved, they have been recognized for their signaling engagements and trafficking abilities, navigating a number of molecules between endosome, Golgi compartments, and the cell surface. Strikingly, recent studies connected all the VPS10p-D receptors to Alzheimer’s disease (AD) development. In addition, they have been also associated with diseases comorbid with AD such as diabetes mellitus and major depressive disorder. This systematic review elaborates on genetic, functional, and mechanistic insights into how dysfunction in VPS10p-D receptors may contribute to AD etiology, AD onset diversity, and AD comorbidities. Starting with their functions in controlling cellular trafficking of amyloid precursor protein and the metabolism of the amyloid beta peptide, we present and exemplify how these receptors, despite being structurally similar, regulate various and distinct cellular events involved in AD. This includes a plethora of signaling crosstalks that impact on neuronal survival, neuronal wiring, neuronal polarity, and synaptic plasticity. Signaling activities of the VPS10p-D receptors are especially linked, but not limited to, the regulation of neuronal fitness and apoptosis via their physical interaction with pro- and mature neurotrophins and their receptors. By compiling the functional versatility of VPS10p-D receptors and their interactions with AD-related pathways, we aim to further propel the AD research towards VPS10p-D receptor family, knowledge that may lead to new diagnostic markers and therapeutic strategies for AD patients.

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High-affinity TrkA and p75 neurotrophin receptor complexes: A twisted affair

Cited by 38 publications

References 139 publications

TrkA Co-Receptors: The Janus Face of TrkA?

TrkA Co-Receptors: The Janus Face of TrkA?

Targeting the Cation-Chloride Co-Transporter NKCC1 to Re-Establish GABAergic Inhibition and an Appropriate Excitatory/Inhibitory Balance in Selective Neuronal Circuits: A Novel Approach for the Treatment of Alzheimer’s Disease

Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer’s disease

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