VEGF-A Stimulates ADAM17-Dependent Shedding of VEGFR2 and Crosstalk Between VEGFR2 and ERK Signaling

被引:144
作者
Swendeman, Steven [1 ]
Mendelson, Karen [1 ,2 ]
Weskamp, Gisela [1 ]
Horiuchi, Keisuke [1 ,4 ]
Deutsch, Urban [5 ]
Scherle, Peggy [6 ]
Hooper, Andrea [3 ]
Rafii, Shahin [3 ]
Blobel, Carl P. [1 ,2 ,3 ]
机构
[1] Hosp Special Surg, Arthrit & Tissue Degenerat Program, New York, NY 10021 USA
[2] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA
[3] Cornell Univ, Weill Med Coll, Dept Cell Biol, New York, NY 10021 USA
[4] Keio Univ, Sch Med, Dept Orthoped Surg, Tokyo, Japan
[5] Univ Bern, Theodor Kocher Inst, CH-3012 Bern, Switzerland
[6] Incyte Corp, Wilmington, DE USA
关键词
D O I
10.1161/CIRCRESAHA.108.184416
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:916 / 918
页数:3
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