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.
- Andreas Fischer
- Andreas Fischer
- Fabian Tetzlaff
- Amitai Menuchin
- David Sprinzak
- Andreas Fischer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Mice were kept under pathogen-free barrier conditions. All animal procedures were performed in accordance with the institutional and national regulations and approved by the local committees for animal experimentation (Heidelberg University and DKFZ) and the local government (Regierungspräsidium Karlsruhe, Germany).(reference number: 35-9185.81/G-30/14 and 35-9185.81/G-259/12).
- Elisabetta Dejana, FIRC Institute of Molecular Oncology, Italy
© 2018, Tetzlaff et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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