title: The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis.
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.
authors: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
authors: Anthony
authors: A
authors: Lanahan
authors: Xi
authors: X
authors: Zhang
authors: Alessandro
authors: A
authors: Fantin
authors: Zhen
authors: Z
authors: Zhuang
authors: Felix
authors: F
authors: Rivera-Molina
authors: Katherine
authors: K
authors: Speichinger
authors: Claudia
authors: C
authors: Prahst
authors: Jiasheng
authors: J
authors: Zhang
authors: Yingdi
authors: Y
authors: Wang
authors: George
authors: G
authors: Davis
authors: Derek
authors: D
authors: Toomre
authors: Christiana
authors: C
authors: Ruhrberg
authors: Michael
authors: M
authors: Simons
mesh_terms: D000818:Animals; D001158:Arteries / Q000166:cytology / Q000503:physiopathology*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D009024:Morphogenesis / Q000502:physiology*; D009389:Neovascularization, Pathologic; D039942:Neuropilin-1 / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction; D014168:Transferrin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D014168:Transferrin; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; C467480:vascular endothelial growth factor A, mouse; D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2
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