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PMID:23639442

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Citation

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 and Simons, M (2013) The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. Dev. Cell 25:156-68

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.

Links

PubMed PMC3774154 Online version:10.1016/j.devcel.2013.03.019

Keywords

Animals; Arteries/cytology; Arteries/physiopathology; Cells, Cultured; Cytoplasm/metabolism; Endocytosis/physiology; Endosomes/metabolism; Endothelium, Vascular/cytology; Endothelium, Vascular/metabolism; MAP Kinase Signaling System; Mice; Morphogenesis/physiology; Neovascularization, Pathologic; Neuropilin-1/physiology; Phosphorylation; Signal Transduction; Transferrin/metabolism; Vascular Endothelial Growth Factor A/genetics; Vascular Endothelial Growth Factor A/metabolism; Vascular Endothelial Growth Factor Receptor-2/genetics; Vascular Endothelial Growth Factor Receptor-2/metabolism; Vesicular Transport Proteins/metabolism

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Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NRP1

located_in

GO:0005769: early endosome

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P97333

C

Seeded From UniProt

complete

HUMAN:NRP1

located_in

GO:0097443: sorting endosome

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P97333

C

Seeded From UniProt

complete

HUMAN:NRP1

involved_in

GO:0001525: angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:NRP1

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRP1

involved_in

GO:0048010: vascular endothelial growth factor receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRP1

involved_in

GO:0038084: vascular endothelial growth factor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRP1

involved_in

GO:1902966: positive regulation of protein localization to early endosome

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRP1

involved_in

GO:0050731: positive regulation of peptidyl-tyrosine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTN1

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:PTN1

located_in

GO:0097443: sorting endosome

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:PTN1

involved_in

GO:0070373: negative regulation of ERK1 and ERK2 cascade

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P97333

P

  • occurs_in:(CL:1000413)

Seeded From UniProt

complete

MOUSE:VGFR2

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:VGFR2

located_in

GO:0097443: sorting endosome

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:VGFR2

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:NRP1

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:NRP1

located_in

GO:0097443: sorting endosome

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:NRP1

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:NRP1

involved_in

GO:0050731: positive regulation of peptidyl-tyrosine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:1000413)
  • part_of:(GO:0038084)
  • has_input:(UniProtKB:P35918)

Seeded From UniProt

complete

MOUSE:NRP1

involved_in

GO:0048844: artery morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0002103)

Seeded From UniProt

complete

MOUSE:VGFR2

part_of

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:VGFR2

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:VGFR2

part_of

GO:0097443: sorting endosome

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:1000413)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:1902966: positive regulation of protein localization to early endosome

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

part_of:(GO:0038084)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0050731: positive regulation of peptidyl-tyrosine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

part_of:(GO:0038084)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0048010: vascular endothelial growth factor receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

part_of:(GO:0038084)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0038084: vascular endothelial growth factor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTN1

involved_in

GO:0030948: negative regulation of vascular endothelial growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P97333

P

  • occurs_in:(CL:1000413)
  • has_input:(UniProtKB:P35918)

Seeded From UniProt

complete

MOUSE:PTN1

involved_in

GO:1990264: peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P97333

P

  • occurs_in:(CL:1000413)
  • has_input:(UniProtKB:P35918)

Seeded From UniProt

complete

MOUSE:PTN1

part_of

GO:0097443: sorting endosome

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:PTN1

involved_in

GO:0070373: negative regulation of ERK1 and ERK2 cascade

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P97333

P

occurs_in:(CL:1000413)

Seeded From UniProt

complete

MOUSE:PTN1

part_of

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:1000413)

Seeded From UniProt

complete

HUMAN:NRP1

involved_in

GO:0048844: artery morphogenesis

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P97333

P

Seeded From UniProt

complete

HUMAN:NRP1

involved_in

GO:0038190: VEGF-activated neuropilin signaling pathway

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P97333

P

Seeded From UniProt

complete

HUMAN:NRP1

part_of

GO:0005769: early endosome

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P97333

C

Seeded From UniProt

complete

HUMAN:NRP1

involved_in

GO:0001525: angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:NRP1

part_of

GO:0097443: sorting endosome

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P97333

C

Seeded From UniProt

complete

HUMAN:NRP1

involved_in

GO:1902946: protein localization to early endosome

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P97333

P

Seeded From UniProt

complete

HUMAN:NRP1

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P97333

P

Seeded From UniProt

complete

MOUSE:NRP1

involved_in

GO:1902946: protein localization to early endosome

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P35918)
  • occurs_in:(CL:0000115)

Seeded From UniProt

complete

MOUSE:NRP1

part_of

GO:0097443: sorting endosome

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:NRP1

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NRP1

involved_in

GO:0060982: coronary artery morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NRP1

involved_in

GO:0050731: positive regulation of peptidyl-tyrosine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:1000413)
  • part_of:(GO:0038084)
  • has_regulation_target:(UniProtKB:P35918)

Seeded From UniProt

complete

MOUSE:NRP1

involved_in

GO:0048844: artery morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(UBERON:0002103)

Seeded From UniProt

complete

MOUSE:NRP1

involved_in

GO:0048010: vascular endothelial growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NRP1

involved_in

GO:0038190: VEGF-activated neuropilin signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NRP1

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:NRP1

part_of

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:1000413)

Seeded From UniProt

complete

MOUSE:NRP1

involved_in

GO:0001525: angiogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:O14786

P

Seeded From UniProt

complete

MOUSE:NRP1

involved_in

GO:0061441: renal artery morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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