VEGF-a stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between vegfr2 and ERK signaling

Steven Swendeman, Karen Mendelson, Gisela Weskamp, Keisuke Horiuchi, Urban Deutsch, Peggy Scherle, Andrea Hooper, Shahin Rafii, Carl P. Blobel

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

Vascular endothelial growth factor (VEGF)-A and the VEGF receptors are critical for regulating angiogenesis during development and homeostasis and in pathological conditions, such as cancer and proliferative retinopathies. Most effects of VEGF-A are mediated by the VEGFR2 and its coreceptor, neuropilin (NRP)-1. Here, we show that VEGFR2 is shed from cells by the metalloprotease disintegrin ADAM17, whereas NRP-1 is released by ADAM10. VEGF-A enhances VEGFR2 shedding by ADAM17 but not shedding of NRP-1 by ADAM10. VEGF-A activates ADAM17 via the extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase pathways, thereby also triggering shedding of other ADAM17 substrates, including tumor necrosis factor α, transforming growth factor α, heparin-binding epidermal growth factor-like growth factor, and Tie-2. Interestingly, an ADAM17-selective inhibitor shortens the duration of VEGF-A-stimulated ERK phosphorylation in human umbilical vein endothelial cells, providing evidence for an ADAM17-dependent crosstalk between the VEGFR2 and ERK signaling. Targeting the sheddases of VEGFR2 or NRP-1 might offer new opportunities to modulate VEGF-A signaling, an already-established target for treatment of pathological neovascularization.

Original languageEnglish
Pages (from-to)916-918
Number of pages3
JournalCirculation Research
Volume103
Issue number9
DOIs
Publication statusPublished - 2008 Oct 24

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Extracellular Signal-Regulated MAP Kinases
Neuropilin-1
Vascular Endothelial Growth Factor A
Pathologic Neovascularization
Disintegrins
Vascular Endothelial Growth Factor Receptor
Human Umbilical Vein Endothelial Cells
Transforming Growth Factors
Metalloproteases
Mitogen-Activated Protein Kinases
Epidermal Growth Factor
Heparin
ADAM17 Protein
Intercellular Signaling Peptides and Proteins
Homeostasis
Tumor Necrosis Factor-alpha
Phosphorylation
Neoplasms

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Swendeman, S., Mendelson, K., Weskamp, G., Horiuchi, K., Deutsch, U., Scherle, P., ... Blobel, C. P. (2008). VEGF-a stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between vegfr2 and ERK signaling. Circulation Research, 103(9), 916-918. https://doi.org/10.1161/CIRCRESAHA.108.184416

VEGF-a stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between vegfr2 and ERK signaling. / Swendeman, Steven; Mendelson, Karen; Weskamp, Gisela; Horiuchi, Keisuke; Deutsch, Urban; Scherle, Peggy; Hooper, Andrea; Rafii, Shahin; Blobel, Carl P.

In: Circulation Research, Vol. 103, No. 9, 24.10.2008, p. 916-918.

Research output: Contribution to journalArticle

Swendeman, S, Mendelson, K, Weskamp, G, Horiuchi, K, Deutsch, U, Scherle, P, Hooper, A, Rafii, S & Blobel, CP 2008, 'VEGF-a stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between vegfr2 and ERK signaling', Circulation Research, vol. 103, no. 9, pp. 916-918. https://doi.org/10.1161/CIRCRESAHA.108.184416
Swendeman, Steven ; Mendelson, Karen ; Weskamp, Gisela ; Horiuchi, Keisuke ; Deutsch, Urban ; Scherle, Peggy ; Hooper, Andrea ; Rafii, Shahin ; Blobel, Carl P. / VEGF-a stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between vegfr2 and ERK signaling. In: Circulation Research. 2008 ; Vol. 103, No. 9. pp. 916-918.
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