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PMID:19033661

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Citation

Zhang, H, He, Y, Dai, S, Xu, Z, Luo, Y, Wan, T, Luo, D, Jones, D, Tang, S, Chen, H, Sessa, WC and Min, W (2008) AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice. J. Clin. Invest. 118:3904-16

Abstract

ASK1-interacting protein-1 (AIP1), a recently identified member of the Ras GTPase-activating protein family, is highly expressed in vascular ECs and regulates EC apoptosis in vitro. However, its function in vivo has not been established. To study this, we generated AIP1-deficient mice (KO mice). Although these mice showed no obvious defects in vascular development, they exhibited dramatically enhanced angiogenesis in 2 models of inflammatory angiogenesis. In one of these models, the enhanced angiogenesis observed in the KO mice was associated with increased VEGF-VEGFR2 signaling. Consistent with this, VEGF-induced ear, cornea, and retina neovascularization were greatly augmented in KO mice and the enhanced retinal angiogenesis was markedly diminished by overexpression of AIP1. In vitro, VEGF-induced EC migration was inhibited by AIP1 overexpression, whereas it was augmented by both AIP1 knockout and knockdown, with the enhanced EC migration caused by AIP1 knockdown being associated with increased VEGFR2 signaling. We present mechanistic data that suggest AIP1 is recruited to the VEGFR2-PI3K complex, binding to both VEGFR2 and PI3K p85, at a late phase of the VEGF response, and that this leads to inhibition of VEGFR2 signaling. Taken together, our data demonstrate that AIP1 functions as an endogenous inhibitor in VEGFR2-mediated adaptive angiogenesis in mice.

Links

PubMed PMC2575835 Online version:10.1172/JCI36168

Keywords

Animals; Cattle; Cell Movement/genetics; Corneal Neovascularization/genetics; Corneal Neovascularization/metabolism; Disease Models, Animal; Endothelial Cells/metabolism; Humans; Inflammation/genetics; Inflammation/metabolism; Mice; Mice, Knockout; Neovascularization, Pathologic/genetics; Neovascularization, Pathologic/metabolism; Organ Specificity/genetics; Phosphatidylinositol 3-Kinases/genetics; Phosphatidylinositol 3-Kinases/metabolism; Signal Transduction/genetics; 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; ras GTPase-Activating Proteins/genetics; ras GTPase-Activating Proteins/metabolism

Significance

Annotations

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

HUMAN:VEGFA

involved_in

GO:0031334: positive regulation of protein-containing complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VGFR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q5VWQ8

F

Seeded From UniProt

complete

MOUSE:DAB2P

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DAB2P

involved_in

GO:0010596: negative regulation of endothelial cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DAB2P

involved_in

GO:0035148: tube formation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DAB2P

involved_in

GO:0001933: negative regulation of protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DAB2P

involved_in

GO:0016525: negative regulation of angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DAB2P

involved_in

GO:0036324: vascular endothelial growth factor receptor-2 signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DAB2P

involved_in

GO:0035924: cellular response to vascular endothelial growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DAB2P

involved_in

GO:1900747: negative regulation of vascular endothelial growth factor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DAB2P

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DAB2P

involved_in

GO:0010596: negative regulation of endothelial cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DAB2P

involved_in

GO:0035148: tube formation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DAB2P

enables

GO:0017124: SH3 domain binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DAB2P

enables

GO:0043184: vascular endothelial growth factor receptor 2 binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35968

F

Seeded From UniProt

complete

HUMAN:DAB2P

enables

GO:0043548: phosphatidylinositol 3-kinase binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DAB2P

involved_in

GO:0016525: negative regulation of angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DAB2P

involved_in

GO:0035924: cellular response to vascular endothelial growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0010595: positive regulation of endothelial cell migration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0031334: positive regulation of protein complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0035148: tube formation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0045766: positive regulation of angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VGFR2

involved_in

GO:0046777: protein autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VGFR2

involved_in

GO:0035924: cellular response to vascular endothelial growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VGFR2

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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