scholarly journals Nradd Acts as a Negative Feedback Regulator of Wnt/β-Catenin Signaling and Promotes Apoptosis

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 100
Author(s):  
Ozgun Ozalp ◽  
Ozge Cark ◽  
Yagmur Azbazdar ◽  
Betul Haykir ◽  
Gokhan Cucun ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Mammalian Cells ◽  
Genetic Disorders ◽  
Negative Regulator ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Death Domain ◽  
C Terminus ◽  
And Function ◽  
Functional Analyses

Wnt/β-catenin signaling controls many biological processes for the generation and sustainability of proper tissue size, organization and function during development and homeostasis. Consequently, mutations in the Wnt pathway components and modulators cause diseases, including genetic disorders and cancers. Targeted treatment of pathway-associated diseases entails detailed understanding of the regulatory mechanisms that fine-tune Wnt signaling. Here, we identify the neurotrophin receptor-associated death domain (Nradd), a homolog of p75 neurotrophin receptor (p75NTR), as a negative regulator of Wnt/β-catenin signaling in zebrafish embryos and in mammalian cells. Nradd significantly suppresses Wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Nradd is localized at the plasma membrane, physically interacts with the Wnt receptor complex and enhances apoptosis in cooperation with Wnt/β-catenin signaling. Our functional analyses indicate that the N-glycosylated N-terminus and the death domain-containing C-terminus regions are necessary for both the inhibition of Wnt signaling and apoptosis. Finally, Nradd can induce apoptosis in mammalian cells. Thus, Nradd regulates cell death as a modifier of Wnt/β-catenin signaling during development.

scholarly journals Calmodulin Regulation of NaV1.4 Current: Role of Binding to the Carboxyl Terminus

2008 ◽  
Vol 131 (3) ◽  
pp. 197-209 ◽  
Author(s):  
Subrata Biswas ◽  
Isabelle Deschênes ◽  
Deborah DiSilvestre ◽  
Yanli Tian ◽  
Victoria L. Halperin ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Surface Membrane ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Na Channel ◽  
Na Current ◽  
Iq Motif ◽  
C Terminus ◽  
Steady State Inactivation ◽  
And Function

Calmodulin (CaM) regulates steady-state inactivation of sodium currents (NaV1.4) in skeletal muscle. Defects in Na current inactivation are associated with pathological muscle conditions such as myotonia and paralysis. The mechanisms of CaM modulation of expression and function of the Na channel are incompletely understood. A physical association between CaM and the intact C terminus of NaV1.4 has not previously been demonstrated. FRET reveals channel conformation-independent association of CaM with the C terminus of NaV1.4 (CT-NaV1.4) in mammalian cells. Mutation of the NaV1.4 CaM-binding IQ motif (NaV1.4IQ/AA) reduces cell surface expression of NaV1.4 channels and eliminates CaM modulation of gating. Truncations of the CT that include the IQ region abolish Na current. NaV1.4 channels with one CaM fused to the CT by variable length glycine linkers exhibit CaM modulation of gating only with linker lengths that allowed CaM to reach IQ region. Thus one CaM is sufficient to modulate Na current, and CaM acts as an ancillary subunit of NaV1.4 channels that binds to the CT in a conformation-independent fashion, modulating the voltage dependence of inactivation and facilitating trafficking to the surface membrane.

scholarly journals Nbr1 Is a Novel Inhibitor of Ligand-Mediated Receptor Tyrosine Kinase Degradation

2010 ◽  
Vol 30 (24) ◽  
pp. 5672-5685 ◽  
Author(s):  
Faraz K. Mardakheh ◽  
Giulio Auciello ◽  
Tim R. Dafforn ◽  
Joshua Z. Rappoport ◽  
John K. Heath
Keyword(s):  
Tyrosine Kinases ◽  
Protein Localization ◽  
Negative Regulator ◽  
Receptor Internalization ◽  
C Terminus ◽  
Late Endosomes ◽  
Exact Function ◽  
Α Helix ◽  
And Function

ABSTRACT Neighbor of BRCA1 (Nbr1) is a highly conserved multidomain scaffold protein with proposed roles in endocytic trafficking and selective autophagy. However, the exact function of Nbr1 in these contexts has not been studied in detail. Here we investigated the role of Nbr1 in the trafficking of receptor tyrosine kinases (RTKs). We report that ectopic Nbr1 expression inhibits the ligand-mediated lysosomal degradation of RTKs, and this is probably done via the inhibition of receptor internalization. Conversely, the depletion of endogenous NBR1 enhances RTK degradation. Analyses of truncation mutations demonstrated that the C terminus of Nbr1 is essential but not sufficient for this activity. Moreover, the C terminus of Nbr1 is essential but not sufficient for the localization of the protein to late endosomes. We demonstrate that the C terminus of Nbr1 contains a novel membrane-interacting amphipathic α-helix, which is essential for the late endocytic localization of the protein but not for its effect on RTK degradation. Finally, autophagic and late endocytic localizations of Nbr1 are independent of one another, suggesting that the roles of Nbr1 in each context might be distinct. Our results define Nbr1 as a negative regulator of ligand-mediated RTK degradation and reveal the interplay between its various regions for protein localization and function.

scholarly journals Death Domain Signaling by Disulfide-Linked Dimers of the p75 Neurotrophin Receptor Mediates Neuronal Death in the CNS

2016 ◽  
Vol 36 (20) ◽  
pp. 5587-5595 ◽  
Author(s):  
K. Tanaka ◽  
C. E. Kelly ◽  
K. Y. Goh ◽  
K. B. Lim ◽  
C. F. Ibanez
Keyword(s):  
Neuronal Death ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Death Domain

scholarly journals Inactive variants of death receptor p75NTR reduce Alzheimer’s neuropathology by interfering with APP internalization

2020 ◽  
Author(s):  
Chenju Yi ◽  
Ket Yin Goh ◽  
Lik-Wei Wong ◽  
Kazuhiro Tanaka ◽  
Sreedharan Sajikumar ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Transmembrane Domain ◽  
Death Receptor ◽  
Amyloid Plaque ◽  
Neurotrophin Receptor ◽  
Plaque Burden ◽  
P75 Neurotrophin Receptor ◽  
Death Domain ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice

AbstractA prevalent model of Alzheimer’s disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. However, the molecular pathways that regulate APP internalization and intracellular trafficking in neurons are unknown. Here we report that 5xFAD mice, an animal model of AD, expressing signaling-deficient variants of the p75 neurotrophin receptor (p75NTR) show greater neuroprotection from AD neuropathology than animals lacking this receptor. p75NTR knock-in mice lacking the death domain or transmembrane Cys259 showed lower levels of Aβ species, amyloid plaque burden, gliosis, mitochondrial stress and neurite dystrophy than global knock-outs. Strikingly, long-term synaptic plasticity and memory, which are completely disrupted in 5xFAD mice, were fully recovered in the knock-in mice. Mechanistically, we found that p75NTR interacts with APP and regulates its internalization in hippocampal neurons. Inactive p75NTR variants internalized much slower and to lower levels than wild type p75NTR, favoring non-amyloidogenic APP cleavage by reducing APP internalization and colocalization with BACE1, the critical protease for generation of neurotoxic APP fragments. These results reveal a novel pathway that directly and specifically regulates APP internalization, amyloidogenic processing and disease progression, and suggest that inhibitors targeting the p75NTR transmembrane domain may be an effective therapeutic strategy in AD.

scholarly journals The RNA Binding Protein Nuclear Factor 90 Functions as Both a Positive and Negative Regulator of Gene Expression in Mammalian Cells

2002 ◽  
Vol 22 (1) ◽  
pp. 343-356 ◽  
Author(s):  
Trevor W. Reichman ◽  
Luis C. Muñiz ◽  
Michael B. Mathews
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Rna Binding ◽  
Interleukin 2 ◽  
Negative Regulator ◽  
Nuclear Factor ◽  
C Terminus ◽  
Inhibit Gene Expression ◽  
Localization Signal ◽  
Major Late Promoter

ABSTRACT Nuclear factor 90 (NF90) was originally isolated in a complex that binds to the antigen recognition response element (ARRE-2) present in the interleukin-2 promoter. To characterize the transcriptional properties of NF90 in mammalian cells, we examined its ability to modulate promoter function in cellular transfection assays. NF90-Gal4 fusion proteins inhibited transcription from the adenovirus major late promoter in a fashion that was dependent on Gal4 targeting. Conversely, NF90 activated the cytomegalovirus immediate-early promoter, to which it was not targeted. These effects required distinct but overlapping domains in the C terminus of NF90, which contains a functional nuclear localization signal and two double-stranded-RNA binding motifs. NF90 is present in cellular complexes together with the NF45 protein. Transfection assays showed that NF45 binds NF90 strongly and stimulates its ability to activate but not to inhibit gene expression. This report characterizes NF90 as both a positive and negative regulator of gene expression, depending on the promoter context, and suggests a role for NF45 as a regulator of NF90.

scholarly journals Interchangeable but Essential Functions of SNX1 and SNX2 in the Association of Retromer with Endosomes and the Trafficking of Mannose 6-Phosphate Receptors

2006 ◽  
Vol 27 (3) ◽  
pp. 1112-1124 ◽  
Author(s):  
Raul Rojas ◽  
Satoshi Kametaka ◽  
Carol R. Haft ◽  
Juan S. Bonifacino
Keyword(s):  
Mammalian Cells ◽  
Human Cell Line ◽  
Sorting Nexin ◽  
Retromer Complex ◽  
Cell Line Hela ◽  
Endosomal Membranes ◽  
Mannose 6 Phosphate ◽  
And Function ◽  
Golgi Network ◽  
Functional Analyses

ABSTRACT The retromer is a cytosolic/peripheral membrane protein complex that mediates the retrieval of the cation-independent mannose 6-phosphate receptor from endosomes to the trans-Golgi network (TGN) in mammalian cells. Previous studies showed that the mammalian retromer comprises three proteins, named Vps26, Vps29, and Vps35, plus the sorting nexin, SNX1. There is conflicting evidence, however, as to whether a homologous sorting nexin, SNX2, is truly a component of the retromer. In addition, the nature of the subunit interactions and assembly of the mammalian retromer complex are poorly understood. We have addressed these issues by performing biochemical and functional analyses of endogenous retromers in the human cell line HeLa. We found that the mammalian retromer complex consists of two autonomously assembling subcomplexes, namely, a Vps26-Vps29-Vps35 obligate heterotrimer and a SNX1/2 alternative heterodimer or homodimer. The association of Vps26-Vps29-Vps35 with endosomes requires the presence of either SNX1 or SNX2, whereas SNX1/2 can be recruited to endosomes independently of Vps26-Vps29-Vps35. We also found that the presence of either SNX1 or SNX2 is essential for the retrieval of the cation-independent mannose 6-phosphate receptor to the TGN. These observations indicate that the mammalian retromer complex assembles by sequential association of SNX1/2 and Vps26-Vps29-Vps35 subcomplexes on endosomal membranes and that SNX1 and SNX2 play interchangeable but essential roles in retromer structure and function.

scholarly journals Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

2019 ◽  
Vol 3 (1) ◽  
Author(s):  
Zoran Boskovic ◽  
Sonja Meier ◽  
Yunpeng Wang ◽  
Michael R. Milne ◽  
Tessa Onraet ◽  
...  
Keyword(s):  
Basal Forebrain ◽  
Neuronal Development ◽  
Critical Role ◽  
Neurotrophin Receptor ◽  
Current Evidence ◽  
P75 Neurotrophin Receptor ◽  
Neurotrophin Receptors ◽  
Cortical Function ◽  
Cholinergic Basal Forebrain ◽  
And Function

Abstract Cholinergic basal forebrain (cBF) neurons are defined by their expression of the p75 neurotrophin receptor (p75NTR) and tropomyosin-related kinase (Trk) neurotrophin receptors in addition to cholinergic markers. It is known that the neurotrophins, particularly nerve growth factor (NGF), mediate cholinergic neuronal development and maintenance. However, the role of neurotrophin signalling in regulating adult cBF function is less clear, although in dementia, trophic signalling is reduced and p75NTR mediates neurodegeneration of cBF neurons. Here we review the current understanding of how cBF neurons are regulated by neurotrophins which activate p75NTR and TrkA, B or C to influence the critical role that these neurons play in normal cortical function, particularly higher order cognition. Specifically, we describe the current evidence that neurotrophins regulate the development of basal forebrain neurons and their role in maintaining and modifying mature basal forebrain synaptic and cortical microcircuit connectivity. Understanding the role neurotrophin signalling plays in regulating the precision of cholinergic connectivity will contribute to the understanding of normal cognitive processes and will likely provide additional ideas for designing improved therapies for the treatment of neurological disease in which cholinergic dysfunction has been demonstrated.

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