The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis

Anthony Lanahan, Xi Zhang, Alessandro Fantin, Zhen Zhuang, Felix Rivera-Molina, Katherine Speichinger, Claudia Prahst, Jiasheng Zhang, Yingdi Wang, George Davis, Derek Toomre, Christiana Ruhrberg, Michael Simons

Research output: Contribution to journalArticle

108 Citations (Scopus)

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 (Nrp1cyto) 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 Y1175, the site involved in activating ERK signaling. The Nrp1cyto mutation also impaired endothelial tubulogenesis invitro, 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.

Original languageEnglish (US)
Pages (from-to)156-168
Number of pages13
JournalDevelopmental Cell
Volume25
Issue number2
DOIs
StatePublished - Apr 29 2013

Fingerprint

Neuropilin-1
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor
Morphogenesis
Blood Vessels
Tail
Mutation
Endosomes
Endocytosis
Defects

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

Cite this

Lanahan, A., Zhang, X., Fantin, A., Zhuang, Z., Rivera-Molina, F., Speichinger, K., ... Simons, M. (2013). The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis. Developmental Cell, 25(2), 156-168. https://doi.org/10.1016/j.devcel.2013.03.019

The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis. / Lanahan, Anthony; Zhang, Xi; Fantin, Alessandro; Zhuang, Zhen; Rivera-Molina, Felix; Speichinger, Katherine; Prahst, Claudia; Zhang, Jiasheng; Wang, Yingdi; Davis, George; Toomre, Derek; Ruhrberg, Christiana; Simons, Michael.

In: Developmental Cell, Vol. 25, No. 2, 29.04.2013, p. 156-168.

Research output: Contribution to journalArticle

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 2013, 'The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis', Developmental Cell, vol. 25, no. 2, pp. 156-168. https://doi.org/10.1016/j.devcel.2013.03.019
Lanahan A, Zhang X, Fantin A, Zhuang Z, Rivera-Molina F, Speichinger K et al. The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis. Developmental Cell. 2013 Apr 29;25(2):156-168. https://doi.org/10.1016/j.devcel.2013.03.019
Lanahan, Anthony ; Zhang, Xi ; Fantin, Alessandro ; Zhuang, Zhen ; Rivera-Molina, Felix ; Speichinger, Katherine ; Prahst, Claudia ; Zhang, Jiasheng ; Wang, Yingdi ; Davis, George ; Toomre, Derek ; Ruhrberg, Christiana ; Simons, Michael. / The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis. In: Developmental Cell. 2013 ; Vol. 25, No. 2. pp. 156-168.
@article{6ed37298a0e143dd9fd2e02a35acd67e,
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 (Nrp1cyto) 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 Y1175, the site involved in activating ERK signaling. The Nrp1cyto mutation also impaired endothelial tubulogenesis invitro, 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.",
author = "Anthony Lanahan and Xi Zhang and Alessandro Fantin and Zhen Zhuang and Felix Rivera-Molina and Katherine Speichinger and Claudia Prahst and Jiasheng Zhang and Yingdi Wang and George Davis and Derek Toomre and Christiana Ruhrberg and Michael Simons",
year = "2013",
month = "4",
day = "29",
doi = "10.1016/j.devcel.2013.03.019",
language = "English (US)",
volume = "25",
pages = "156--168",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis

AU - Lanahan, Anthony

AU - Zhang, Xi

AU - Fantin, Alessandro

AU - Zhuang, Zhen

AU - Rivera-Molina, Felix

AU - Speichinger, Katherine

AU - Prahst, Claudia

AU - Zhang, Jiasheng

AU - Wang, Yingdi

AU - Davis, George

AU - Toomre, Derek

AU - Ruhrberg, Christiana

AU - Simons, Michael

PY - 2013/4/29

Y1 - 2013/4/29

N2 - 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 (Nrp1cyto) 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 Y1175, the site involved in activating ERK signaling. The Nrp1cyto mutation also impaired endothelial tubulogenesis invitro, 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.

AB - 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 (Nrp1cyto) 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 Y1175, the site involved in activating ERK signaling. The Nrp1cyto mutation also impaired endothelial tubulogenesis invitro, 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.

UR - http://www.scopus.com/inward/record.url?scp=84876976777&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876976777&partnerID=8YFLogxK

U2 - 10.1016/j.devcel.2013.03.019

DO - 10.1016/j.devcel.2013.03.019

M3 - Article

VL - 25

SP - 156

EP - 168

JO - Developmental Cell

JF - Developmental Cell

SN - 1534-5807

IS - 2

ER -