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(Circulation Research. 2008;103:916.)
© 2008 American Heart Association, Inc.

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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

From the Arthritis and Tissue Degeneration Program (S.S., K.M., G.W., K.H., C.P.B.), The Hospital for Special Surgery; Department of Physiology and Biophysics (K.M., C.P.B.) and Department Cell Biology (A.H., S.R., C.P.B.), Weill Medical College of Cornell University, New York; Department of Orthopedic Surgery (K.H.), Keio University, School of Medicine, Tokyo, Japan; and Theodor Kocher Institute (U.D.), University of Bern, Switzerland; and Incyte Corporation (P.S.), Wilmington, Del.

Correspondence to Dr Carl P. Blobel, Arthritis and Tissue Degeneration Program, Caspary Research Building, Room 426, Hospital for Special Surgery, 535 E 70th St, New York, NY, 10021. E-mail blobelc{at}hss.edu

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 , transforming growth factor , 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.

Key Words: ADAM17 • ectodomain shedding • VEGFR2 • Tie-2 • neuropilin-1

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