The Role of Intracellular Trafficking of Notch Receptors in Ligand-Independent Notch Activation

J. Hounjet; M. Vooijs

doi:10.3390/biom11091369

The Role of Intracellular Trafficking of Notch Receptors in Ligand-Independent Notch Activation

J. Hounjet, M. Vooijs^*

^*Corresponding author for this work

Research output: Contribution to journal › (Systematic) Review article › peer-review

Abstract

Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities in normal tissues. Therefore, there is an unmet need to discover novel regulators of malignant Notch signaling, which do not affect Notch signaling in healthy tissues. This review provides a comprehensive overview of the current knowledge on the role of intracellular trafficking in ligand-independent Notch receptor activation, the possible mechanisms involved, and possible therapeutic opportunities for inhibitors of intracellular trafficking in Notch targeting.

Original language	English
Article number	1369
Number of pages	23
Journal	Biomolecules
Volume	11
Issue number	9
DOIs	https://doi.org/10.3390/biom11091369
Publication status	Published - 1 Sept 2021

Keywords

Drosophila
Notch signaling
intracellular trafficking
ligand-independent
mammals
therapeutic targeting
GAMMA-SECRETASE INHIBITOR
PROTEOLYTIC ACTIVATION
TRANSMEMBRANE DOMAIN
AMYLOID PRECURSOR PROTEIN
ENDOCYTIC TRAFFICKING
ENDOSOMAL TRAFFICKING
DEPENDENT CLEAVAGE
RETROGRADE TRANSPORT
REGULATORY REGION
DROSOPHILA DELTEX

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10.3390/biom11091369Licence: CC BY

Cite this

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title = "The Role of Intracellular Trafficking of Notch Receptors in Ligand-Independent Notch Activation",

abstract = "Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities in normal tissues. Therefore, there is an unmet need to discover novel regulators of malignant Notch signaling, which do not affect Notch signaling in healthy tissues. This review provides a comprehensive overview of the current knowledge on the role of intracellular trafficking in ligand-independent Notch receptor activation, the possible mechanisms involved, and possible therapeutic opportunities for inhibitors of intracellular trafficking in Notch targeting.",

keywords = "Drosophila, Notch signaling, intracellular trafficking, ligand-independent, mammals, therapeutic targeting, GAMMA-SECRETASE INHIBITOR, PROTEOLYTIC ACTIVATION, TRANSMEMBRANE DOMAIN, AMYLOID PRECURSOR PROTEIN, ENDOCYTIC TRAFFICKING, ENDOSOMAL TRAFFICKING, DEPENDENT CLEAVAGE, RETROGRADE TRANSPORT, REGULATORY REGION, DROSOPHILA DELTEX",

author = "J. Hounjet and M. Vooijs",

note = "Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

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doi = "10.3390/biom11091369",

language = "English",

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AU - Vooijs, M.

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N2 - Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities in normal tissues. Therefore, there is an unmet need to discover novel regulators of malignant Notch signaling, which do not affect Notch signaling in healthy tissues. This review provides a comprehensive overview of the current knowledge on the role of intracellular trafficking in ligand-independent Notch receptor activation, the possible mechanisms involved, and possible therapeutic opportunities for inhibitors of intracellular trafficking in Notch targeting.

AB - Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities in normal tissues. Therefore, there is an unmet need to discover novel regulators of malignant Notch signaling, which do not affect Notch signaling in healthy tissues. This review provides a comprehensive overview of the current knowledge on the role of intracellular trafficking in ligand-independent Notch receptor activation, the possible mechanisms involved, and possible therapeutic opportunities for inhibitors of intracellular trafficking in Notch targeting.

KW - Drosophila

KW - Notch signaling

KW - intracellular trafficking

KW - ligand-independent

KW - mammals

KW - therapeutic targeting

KW - GAMMA-SECRETASE INHIBITOR

KW - PROTEOLYTIC ACTIVATION

KW - TRANSMEMBRANE DOMAIN

KW - AMYLOID PRECURSOR PROTEIN

KW - ENDOCYTIC TRAFFICKING

KW - ENDOSOMAL TRAFFICKING

KW - DEPENDENT CLEAVAGE

KW - RETROGRADE TRANSPORT

KW - REGULATORY REGION

KW - DROSOPHILA DELTEX

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DO - 10.3390/biom11091369

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