title: Synaptojanin-2 binding protein stabilizes the Notch ligands DLL1 and DLL4 and inhibits sprouting angiogenesis.
abstract: BACKGROUND
  The formation of novel blood vessels is initiated by vascular endothelial growth factor. Subsequently, DLL4-Notch signaling controls the selection of tip cells, which guide new sprouts, and trailing stalk cells. Notch signaling in stalk cells is induced by DLL4 on the tip cells. Moreover, DLL4 and DLL1 are expressed in the stalk cell plexus to maintain Notch signaling. Notch loss-of-function causes formation of a hyperdense vascular network with disturbed blood flow.
  
  
  OBJECTIVE
  This study was aimed at identifying novel modifiers of Notch signaling that interact with the intracellular domains of DLL1 and DLL4.
  
  
  RESULTS
  Synaptojanin-2 binding protein (SYNJ2BP, also known as ARIP2) interacted with the PDZ binding motif of DLL1 and DLL4, but not with the Notch ligand Jagged-1. SYNJ2BP was preferentially expressed in stalk cells, enhanced DLL1 and DLL4 protein stability, and promoted Notch signaling in endothelial cells. SYNJ2BP induced expression of the Notch target genes HEY1, lunatic fringe (LFNG), and ephrin-B2, reduced phosphorylation of ERK1/2, and decreased expression of the angiogenic factor vascular endothelial growth factor (VEGF)-C. It inhibited the expression of genes enriched in tip cells, such as angiopoietin-2, ESM1, and Apelin, and impaired tip cell formation. SYNJ2BP inhibited endothelial cell migration, proliferation, and VEGF-induced angiogenesis. This could be rescued by blockade of Notch signaling or application of angiopoietin-2. SYNJ2BP-silenced human endothelial cells formed a functional vascular network in immunocompromised mice with significantly increased vascular density.
  
  
  CONCLUSIONS
  These data identify SYNJ2BP as a novel inhibitor of tip cell formation, executing its functions predominately by promoting Delta-Notch signaling.
authors.affiliation: From Division of Vascular Signaling and Cancer (M.G.A., C.B., A.F., W.-J.Y., S.E.H., A.F.) and Division of Vascular Oncology and Metastasis (S.G., H.G.A.), German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany; Division of Vascular Biology and Tumor Angiogenesis (M.G.A., C.B., W.-J.Y., J.W.-L., S.E.H., M.P., H.G.A., A.F.) and Fifth Medical Department (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; and BioNTech AG, Mainz, Germany (J.W.-L.).
authors.forename: M Gordian
authors.initials: MG
authors.lastname: Adam
authors.forename: Caroline
authors.initials: C
authors.lastname: Berger
authors.forename: Anja
authors.initials: A
authors.lastname: Feldner
authors.forename: Wan-Jen
authors.initials: WJ
authors.lastname: Yang
authors.forename: Joycelyn
authors.initials: J
authors.lastname: Wüstehube-Lausch
authors.forename: Stefanie E
authors.initials: SE
authors.lastname: Herberich
authors.forename: Marcel
authors.initials: M
authors.lastname: Pinder
authors.forename: Sabine
authors.initials: S
authors.lastname: Gesierich
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hammes
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Andreas
authors.initials: A
authors.lastname: Fischer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C512941:DLK1 protein, human; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C111442:MPDZ protein, human; D008565:Membrane Proteins; D051880:Receptors, Notch; C486752:SYNJ2BP protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: DLL4; Notch; SYNJ2BP; angiogenesis; blood vessels; endothelial cell differentiation