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

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.

Research on Alpine Landscape Development: From Research to Policy

Swiss National Research Programs (NRPs) are usually geared to addressing issues of major societal concern. In so doing these programs produce different kinds of knowledge: analytical knowledge necessary for revealing the driving forces, conflicting interests and institutional settings that govern the processes under scrutiny; target knowledge oriented towards revealing the directions in which the processes should be guided; and action knowledge that informs about the means by which this can best be achieved. Analytical knowledge answers the questions “what is the problem?” and “what causes it?” while target knowledge helps to define “what is our vision for the future?” and action knowledge deals with “how can we solve the problem?” Production of these 3 different types of knowledge is usually linked in an iterative process in the course of the research supported in an NRP.

EU and Swiss regulatory action on Nanomaterials

Dannie Jost lectured on EU and Swiss regulatory action on nanomaterials as one of 16 speakers at the interdisciplinary seminar for young scientists was aimed at doctoral students from NRP 62 "Smart Materials" and NRP 64 "Opportunities and Risks of Nanomaterials".