MPDZ promotes DLL4-induced Notch signaling during angiogenesis

  1. Fabian Tetzlaff
  2. M Gordian Adam
  3. Anja Feldner
  4. Iris Moll
  5. Amitai Menuchin
  6. Juan Rodriguez-Vita
  7. David Sprinzak
  8. Andreas Fischer  Is a corresponding author
  1. German Cancer Research Center, Germany
  2. Tel Aviv University, Israel

Abstract

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.

Article and author information

Author details

  1. Fabian Tetzlaff

    Division Vascular Signaling and Cancer, German Cancer Research Center, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. M Gordian Adam

    Division Vascular Signaling and Cancer, German Cancer Research Center, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Anja Feldner

    Division Vascular Signaling and Cancer, German Cancer Research Center, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Iris Moll

    Division Vascular Signaling and Cancer, German Cancer Research Center, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Amitai Menuchin

    Department of Biochemistry and Molecular Biology, Wise Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Juan Rodriguez-Vita

    Division Vascular Signaling and Cancer, German Cancer Research Center, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9547-5508
  7. David Sprinzak

    Department of Biochemistry and Molecular Biology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6776-6957
  8. Andreas Fischer

    Division Vascular Signaling and Cancer, German Cancer Research Center, Heidelberg, Germany
    For correspondence
    a.fischer@dkfz.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4889-0909

Funding

Deutsche Forschungsgemeinschaft (SFB-TR23 (A7))

  • Andreas Fischer

Helmholtz-Gemeinschaft

  • Andreas Fischer

Cooperation program in cancer research (CA156)

  • 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.

Ethics

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).

Reviewing Editor

  1. Elisabetta Dejana, FIRC Institute of Molecular Oncology, Italy

Publication history

  1. Received: October 16, 2017
  2. Accepted: April 4, 2018
  3. Accepted Manuscript published: April 5, 2018 (version 1)
  4. Version of Record published: May 3, 2018 (version 2)
  5. Version of Record updated: September 19, 2018 (version 3)

Copyright

© 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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  1. Fabian Tetzlaff
  2. M Gordian Adam
  3. Anja Feldner
  4. Iris Moll
  5. Amitai Menuchin
  6. Juan Rodriguez-Vita
  7. David Sprinzak
  8. Andreas Fischer
(2018)
MPDZ promotes DLL4-induced Notch signaling during angiogenesis
eLife 7:e32860.
https://doi.org/10.7554/eLife.32860
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