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MPDZ promotes DLL4-induced Notch signaling during angiogenesis

Angiogenesis is coordinated by VEGF and Notch signaling. DLL4-induced Notch signaling inhibits tip cell formation and vessel branching. To ensure proper Notch signaling, receptors and ligands are clustered at adherens junctions. However, little is known about factors that control Notch activity by i...

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Autores principales: Tetzlaff, Fabian, Adam, M Gordian, Feldner, Anja, Moll, Iris, Menuchin, Amitai, Rodriguez-Vita, Juan, Sprinzak, David, Fischer, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933922/
https://www.ncbi.nlm.nih.gov/pubmed/29620522
http://dx.doi.org/10.7554/eLife.32860
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author Tetzlaff, Fabian
Adam, M Gordian
Feldner, Anja
Moll, Iris
Menuchin, Amitai
Rodriguez-Vita, Juan
Sprinzak, David
Fischer, Andreas
author_facet Tetzlaff, Fabian
Adam, M Gordian
Feldner, Anja
Moll, Iris
Menuchin, Amitai
Rodriguez-Vita, Juan
Sprinzak, David
Fischer, Andreas
author_sort Tetzlaff, Fabian
collection PubMed
description Angiogenesis is coordinated by VEGF and Notch signaling. DLL4-induced Notch signaling inhibits tip cell formation and vessel branching. To ensure proper Notch signaling, receptors and ligands are clustered at adherens junctions. However, little is known about factors that control Notch activity by influencing the cellular localization of Notch ligands. Here, we show that the multiple PDZ domain protein (MPDZ) enhances Notch signaling activity. MPDZ physically interacts with the intracellular carboxyterminus of DLL1 and DLL4 and enables their interaction with the adherens junction protein Nectin-2. Inactivation of the MPDZ gene leads to impaired Notch signaling activity and increased blood vessel sprouting in cellular models and the embryonic mouse hindbrain. Tumor angiogenesis was enhanced upon endothelial-specific inactivation of MPDZ leading to an excessively branched and poorly functional vessel network resulting in tumor hypoxia. As such, we identified MPDZ as a novel modulator of Notch signaling by controlling ligand recruitment to adherens junctions.
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spelling pubmed-59339222018-05-07 MPDZ promotes DLL4-induced Notch signaling during angiogenesis Tetzlaff, Fabian Adam, M Gordian Feldner, Anja Moll, Iris Menuchin, Amitai Rodriguez-Vita, Juan Sprinzak, David Fischer, Andreas eLife Cancer Biology Angiogenesis is coordinated by VEGF and Notch signaling. DLL4-induced Notch signaling inhibits tip cell formation and vessel branching. To ensure proper Notch signaling, receptors and ligands are clustered at adherens junctions. However, little is known about factors that control Notch activity by influencing the cellular localization of Notch ligands. Here, we show that the multiple PDZ domain protein (MPDZ) enhances Notch signaling activity. MPDZ physically interacts with the intracellular carboxyterminus of DLL1 and DLL4 and enables their interaction with the adherens junction protein Nectin-2. Inactivation of the MPDZ gene leads to impaired Notch signaling activity and increased blood vessel sprouting in cellular models and the embryonic mouse hindbrain. Tumor angiogenesis was enhanced upon endothelial-specific inactivation of MPDZ leading to an excessively branched and poorly functional vessel network resulting in tumor hypoxia. As such, we identified MPDZ as a novel modulator of Notch signaling by controlling ligand recruitment to adherens junctions. eLife Sciences Publications, Ltd 2018-04-05 /pmc/articles/PMC5933922/ /pubmed/29620522 http://dx.doi.org/10.7554/eLife.32860 Text en © 2018, Tetzlaff et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Tetzlaff, Fabian
Adam, M Gordian
Feldner, Anja
Moll, Iris
Menuchin, Amitai
Rodriguez-Vita, Juan
Sprinzak, David
Fischer, Andreas
MPDZ promotes DLL4-induced Notch signaling during angiogenesis
title MPDZ promotes DLL4-induced Notch signaling during angiogenesis
title_full MPDZ promotes DLL4-induced Notch signaling during angiogenesis
title_fullStr MPDZ promotes DLL4-induced Notch signaling during angiogenesis
title_full_unstemmed MPDZ promotes DLL4-induced Notch signaling during angiogenesis
title_short MPDZ promotes DLL4-induced Notch signaling during angiogenesis
title_sort mpdz promotes dll4-induced notch signaling during angiogenesis
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933922/
https://www.ncbi.nlm.nih.gov/pubmed/29620522
http://dx.doi.org/10.7554/eLife.32860
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