MPDZ promotes DLL4-induced Notch signaling during angiogenesis

Elife. 2018 Apr 5;7:e32860. doi: 10.7554/eLife.32860.

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.

Keywords: MPDZ; Notch signaling; angiogenesis; cancer; cancer biology; endothelial cells; human biology; medicine; mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins
  • Carcinoma, Lewis Lung / blood supply*
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / pathology
  • Carrier Proteins / physiology*
  • Cells, Cultured
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Melanoma, Experimental / blood supply*
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology*
  • Neovascularization, Physiologic*
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Signal Transduction

Substances

  • Calcium-Binding Proteins
  • Carrier Proteins
  • DLL4 protein, mouse
  • Dlk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Mpdz protein, mouse
  • Receptors, Notch

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.