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Publication Detail
The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Lanahan A, Zhang X, Fantin A, Zhuang Z, Rivera-Molina F, Speichinger K, Prahst C, Zhang J, Wang Y, Davis G, Toomre D, Ruhrberg C, Simons M
  • Publication date:
    29/04/2013
  • Pagination:
    156, 168
  • Journal:
    Dev Cell
  • Volume:
    25
  • Issue:
    2
  • Status:
    Published
  • Country:
    United States
  • PII:
    S1534-5807(13)00190-1
  • Language:
    eng
  • Keywords:
    Animals, Arteries, Cells, Cultured, Cytoplasm, Endocytosis, Endosomes, Endothelium, Vascular, MAP Kinase Signaling System, Mice, Morphogenesis, Neovascularization, Pathologic, Neuropilin-1, Phosphorylation, Signal Transduction, Transferrin, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Vesicular Transport Proteins
Abstract
Neuropilin 1 (NRP1) plays an important but ill-defined role in VEGF-A signaling and vascular morphogenesis. We show that mice with a knockin mutation that ablates the NRP1 cytoplasmic tail (Nrp1(cyto)) have normal angiogenesis but impaired developmental and adult arteriogenesis. The arteriogenic defect was traced to the absence of a PDZ-dependent interaction between NRP1 and VEGF receptor 2 (VEGFR2) complex and synectin, which delayed trafficking of endocytosed VEGFR2 from Rab5+ to EAA1+ endosomes. This led to increased PTPN1 (PTP1b)-mediated dephosphorylation of VEGFR2 at Y(1175), the site involved in activating ERK signaling. The Nrp1(cyto) mutation also impaired endothelial tubulogenesis in vitro, which could be rescued by expressing full-length NRP1 or constitutively active ERK. These results demonstrate that the NRP1 cytoplasmic domain promotes VEGFR2 trafficking in a PDZ-dependent manner to regulate arteriogenic ERK signaling and establish a role for NRP1 in VEGF-A signaling during vascular morphogenesis.
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