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 (2008). VEGF-A stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signaling. Circulation research, 103(9), pp. 916-8. Baltimore, Md.: Lippincott Williams & Wilkins 10.1161/CIRCRESAHA.108.184416

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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 alpha, transforming growth factor alpha, 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Deutsch, Urban

ISSN:

0009-7330

ISBN:

18818406

Publisher:

Lippincott Williams & Wilkins

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:05

Last Modified:

04 May 2014 23:20

Publisher DOI:

10.1161/CIRCRESAHA.108.184416

PubMed ID:

18818406

Web of Science ID:

000260308500006

URI:

https://boris.unibe.ch/id/eprint/28201 (FactScience: 118528)

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