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A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells

The Notch receptor is an evolutionarily highly conserved transmembrane protein essential to a wide spectrum of cellular systems, and its deregulation has been linked to a vast number of developmental disorders and malignancies. Regulated Notch function is critical for the generation of T-cells, in w...

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Autores principales: Steinbuck, Martin Peter, Winandy, Susan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992298/
https://www.ncbi.nlm.nih.gov/pubmed/29910816
http://dx.doi.org/10.3389/fimmu.2018.01230
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author Steinbuck, Martin Peter
Winandy, Susan
author_facet Steinbuck, Martin Peter
Winandy, Susan
author_sort Steinbuck, Martin Peter
collection PubMed
description The Notch receptor is an evolutionarily highly conserved transmembrane protein essential to a wide spectrum of cellular systems, and its deregulation has been linked to a vast number of developmental disorders and malignancies. Regulated Notch function is critical for the generation of T-cells, in which abnormal Notch signaling results in leukemia. Notch activation through trans-activation of the receptor by one of its ligands expressed on adjacent cells has been well defined. In this canonical ligand-dependent pathway, Notch receptor undergoes conformational changes upon ligand engagement, stimulated by a pulling-force on the extracellular fragment of Notch that results from endocytosis of the receptor-bound ligand into the ligand-expressing cell. These conformational changes in the receptor allow for two consecutive proteolytic cleavage events to occur, which release the intracellular region of the receptor into the cytoplasm. It can then travel to the nucleus, where it induces gene transcription. However, there is accumulating evidence that other pathways may induce Notch signaling. A ligand-independent mechanism of Notch activation has been described in which receptor processing is initiated via cell-internal signals. These signals result in the internalization of Notch into endosomal compartments, where chemical changes existing in this microenvironment result in the conformational modifications required for receptor processing. This review will present mechanisms underlying both canonical ligand-dependent and non-canonical ligand-independent Notch activation pathways and discuss the latter in the context of Notch signaling in T-cells.
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spelling pubmed-59922982018-06-15 A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells Steinbuck, Martin Peter Winandy, Susan Front Immunol Immunology The Notch receptor is an evolutionarily highly conserved transmembrane protein essential to a wide spectrum of cellular systems, and its deregulation has been linked to a vast number of developmental disorders and malignancies. Regulated Notch function is critical for the generation of T-cells, in which abnormal Notch signaling results in leukemia. Notch activation through trans-activation of the receptor by one of its ligands expressed on adjacent cells has been well defined. In this canonical ligand-dependent pathway, Notch receptor undergoes conformational changes upon ligand engagement, stimulated by a pulling-force on the extracellular fragment of Notch that results from endocytosis of the receptor-bound ligand into the ligand-expressing cell. These conformational changes in the receptor allow for two consecutive proteolytic cleavage events to occur, which release the intracellular region of the receptor into the cytoplasm. It can then travel to the nucleus, where it induces gene transcription. However, there is accumulating evidence that other pathways may induce Notch signaling. A ligand-independent mechanism of Notch activation has been described in which receptor processing is initiated via cell-internal signals. These signals result in the internalization of Notch into endosomal compartments, where chemical changes existing in this microenvironment result in the conformational modifications required for receptor processing. This review will present mechanisms underlying both canonical ligand-dependent and non-canonical ligand-independent Notch activation pathways and discuss the latter in the context of Notch signaling in T-cells. Frontiers Media S.A. 2018-06-01 /pmc/articles/PMC5992298/ /pubmed/29910816 http://dx.doi.org/10.3389/fimmu.2018.01230 Text en Copyright © 2018 Steinbuck and Winandy. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Steinbuck, Martin Peter
Winandy, Susan
A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells
title A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells
title_full A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells
title_fullStr A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells
title_full_unstemmed A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells
title_short A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells
title_sort review of notch processing with new insights into ligand-independent notch signaling in t-cells
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992298/
https://www.ncbi.nlm.nih.gov/pubmed/29910816
http://dx.doi.org/10.3389/fimmu.2018.01230
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