Regulated Intramembrane Proteolysis of the p75 Neurotrophin Receptor Modulates Its Association with the TrkA Receptor

Jung, Kwang-Mook; Tan, Serena; Landman, Natalie; Petrova, Kseniya; Murray, Simon S.; Lewis, R. A.; Kim, Peter K.; Kim, Dae Sup; Ryu, Sung Ho; Chao, Moses V.; Kim, Tae‐Wan

doi:10.1074/jbc.m306028200

Cited by 190 publications

(208 citation statements)

References 45 publications

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“…p75 NTR undergoes sequential proteolytic cleavage by a-secretase and c-secretase activities, releasing its intracellular domain (ICD) into the cytoplasm, in a manner analogous to the cleavage-dependent signaling pathway of Notch and b-amyloid precursor protein (Jung et al, 2003;Kanning et al, 2003). Cytoplasmic release of the p75 NTR ICD by this pathway promotes signaling by associated NRIF (Kenchappa et al, 2006).…”

Section: The Neurotrophin Receptors: a Brief Summary Of Signaling Mecmentioning

confidence: 99%

Neurotrophin receptors: Old friends with new partners

Schecterson

Bothwell

2010

Developmental Neurobiology

105

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ABSTRACT:Neurotrophins are important regulators of embryonic development and adult function of most populations of neurons in vertebrate nervous systems. This signaling system regulates many diverse activities, including survival, axon outgrowth, and synaptic plasticity. In mammals, neurotrophin action is mediated by four receptors, p75 NTR , TrkA, TrkB, and TrkC. Although early studies viewed these receptors as solitary agents in the cells outer membrane, recent discoveries reveal that the cell outer membrane is a crowded and highly interactive neighborhood. Neurotrophin receptors partner with a diverse array of membrane proteins, dramatically expanding their functional repertoire. This review will focus on some of the most recent discoveries concerning the promiscuous partnering of neurotrophin receptors. '

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Section: The Neurotrophin Receptors: a Brief Summary Of Signaling Mecmentioning

confidence: 99%

Neurotrophin receptors: Old friends with new partners

Schecterson

Bothwell

2010

Developmental Neurobiology

105

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“…We also determined the amino-terminal amino acid sequence of holo Alc␣1. The determined sequence was ARVNK, which is identical to the Ala 29 -Arg-Val-Asn-Lys 33 sequence. This indi- 38 and Glu 39 to generate FLAG-Alc␣1.…”

Section: Secretion Of A␤-like Peptide and Release Of The Intracellulamentioning

confidence: 99%

“…Supporting this, we demonstrated here that Alc is a novel substrate of ␥-secretase. Recent publications have reported that a number of membrane proteins can act as ␥-secretase substrates (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Thus, it is now clear that there are a variety of ␥-secretase substrates and that ␥-secretase is not specific for APP and Notch (42).…”

Section: Stabilization and Localization Of Alcicd By Interacting Withmentioning

confidence: 99%

Coordinated Metabolism of Alcadein and Amyloid β-Protein Precursor Regulates FE65-dependent Gene Transactivation

Araki

Miyagi

Kato

et al. 2004

Journal of Biological Chemistry

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The Alcadeins (Alcs)/calsyntenins and the amyloid ␤-protein precursor (APP) associate with each other in the brain by binding via their cytoplasmic domains to X11L (the X11-like protein). We previously reported that the formation of this APP-X11L-Alc tripartite complex suppresses the metabolic cleavages of APP. We show here that the metabolism of the Alcs markedly resembles that of APP. The Alcs are subjected to a primary cleavage event that releases their extracellular domain. Alcs then undergo a secondary presenilin-dependent ␥-cleavage that leads to the secretion of the amyloid ␤-protein-like peptide and the liberation of an intracellular domain fragment (AlcICD). However, when Alc is in the tripartite complex, it escapes from these cleavages, as does APP. We also found that AlcICD suppressed the FE65-dependent gene transactivation activity of the APP intracellular domain fragment, probably because AlcICD competes with the APP intracellular domain fragment for binding to FE65. We propose that the Alcs and APP are coordinately metabolized in neurons and that their cleaved cytoplasmic fragments are reciprocally involved in the regulation of FE65-dependent gene transactivation. Any imbalance in the metabolism of Alcs and APP may influence the FE65-dependent gene transactivation, which together with increased secretion of amyloid ␤-protein may contribute to neural disorders.The deposition and accumulation of amyloid ␤-protein (A␤) 1 in the human brain are hallmarks of Alzheimer's disease (AD)(1). Amyloid ␤-protein precursor (APP) is the precursor of A␤. It has a receptor-like transmembrane protein structure that consists of an extracellular domain, a transmembrane domain, and a short carboxyl-terminal cytoplasmic domain (2). The cytoplasmic domain of APP controls its metabolism and various physiological functions by interacting with cytoplasmic adaptor proteins (3-8). One of these adaptor proteins is X11L (the X11-like protein), which associates with the cytoplasmic domain of APP and stabilizes APP metabolism (5, 9). During our previous research that aimed to reveal the molecular mechanism by which X11L regulates APP metabolism, we found that the Alcadeins, which form cadherin-related membrane protein family, are X11-and X11L-binding proteins (9). These proteins are also known as calsyntenins, which were originally isolated as postsynaptic Ca 2ϩ -binding membrane proteins, but whose functions were not identified (10, 11). The Alcadeins (Alcs) consist of two Alc␣ isoforms (Alc␣1 and Alc␣2) and Alc␤ and Alc␥, all of which are type I transmembrane proteins and contain a conserved X11L-binding motif in their single cytoplasmic domains, similar to APP (9).Alc does not directly interact with the cytoplasmic domain of APP. Rather, the association between the two molecules is bridged by the phosphotyrosine interaction domain of X11L. This results in the formation of a tripartite complex in the brain (9). The formation of this complex enhances the X11L-mediated stabilization of APP metabolism and suppresses the generation...

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“…p75 NTR coding sequences were then cloned between the EcoRV and NheI restriction sites of pCDNA3-YFP/CFP to generate in-frame fusion proteins. p75 NTR tm,icd (251-425) was constructed as previously described (24) and fused to YFP as described above. To generate sortilin-YFP, full-length human sortilin, including the sequences encoding the signal and pro-peptides, and the Kozak sequence were amplified by PCR, thereby generating a 3Ј-Kpn site and a 5Ј-Nhe site.…”

Section: Methodsmentioning

confidence: 99%

Mapping of the Interaction Site between Sortilin and the p75 Neurotrophin Receptor Reveals a Regulatory Role for the Sortilin Intracellular Domain in p75 Neurotrophin Receptor Shedding and Apoptosis

Skeldal

Sykes

Glerup

et al. 2012

Journal of Biological Chemistry

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Background: Sortilin and p75NTR induce neuronal apoptosis by binding pro-neurotrophins during development and following neuronal injury. Results: Sortilin interacts with an extracellular juxtamembrane 23-amino acid sequence of p75 NTR . Conclusion: Despite binding being mediated through extracellular interactions, the intracellular domain of sortilin regulates p75 NTR shedding and apoptosis. Significance: Mapping may allow design of compounds inhibiting neuronal cell death by blocking the interaction between sortilin and p75 NTR .

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Regulated Intramembrane Proteolysis of the p75 Neurotrophin Receptor Modulates Its Association with the TrkA Receptor

Cited by 190 publications

References 45 publications

Neurotrophin receptors: Old friends with new partners

Neurotrophin receptors: Old friends with new partners

Coordinated Metabolism of Alcadein and Amyloid β-Protein Precursor Regulates FE65-dependent Gene Transactivation

Mapping of the Interaction Site between Sortilin and the p75 Neurotrophin Receptor Reveals a Regulatory Role for the Sortilin Intracellular Domain in p75 Neurotrophin Receptor Shedding and Apoptosis

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