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Finding New Partnerships: The Function of Individual Extracellular Receptor Domains in Angiogenic Signalling by VEGF Receptors

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Molecular Mechanisms of Angiogenesis

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Abstract

Vascular endothelial growth factors (VEGFs) constitute a family of polypeptides regulating blood and lymphatic vessel development. VEGFs bind to type V receptor tyrosine kinases (RTKs), VEGFR-1, VEGFR-2, and VEGFR-3, but also bind directly to neuropilins and heparan sulphate glycosaminoglycans (HSPG), or indirectly to co-receptors such integrins and semaphorins. VEGFR activation results from ligand-induced dimerisation, which is mediated by the extracellular receptor domain (ECD). Recent studies established that dimerisation is necessary, but not sufficient, for receptor activation, since it was shown that only distinct orientations of receptor monomers give rise to active receptor dimers that are capable to instigate transmembrane signalling. Additional complexity in VEGFR signalling arises from association with specific co-receptors, which is determined by ligand- and ECD-specific interaction domains.

In the following, the role of the different extracellular subdomains in VEGFR activation and signalling is discussed. We give an overview of the mechanistic concepts arising from recent structural studies that led to the development of novel allosteric receptor inhibitors and discuss their possible application in therapies aimed at pathological angiogenesis.

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Acknowledgements

The authors thank Swiss National Science Foundation (grant 31003A-130463 issued to K.B.–H. and PMCDP3-134208/1 issued to C.A.C.H.), Oncosuisse (grant OC2 01200-08-2007 issued to K.B.–H.) and NOVARTIS Stiftung für medizinisch-biologische Forschung (grant 10C61 issued to K.B.–H.).

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Authors and Affiliations

  1. Paul Scherrer Institute, Biomolecular Research, Molecular cell Biology, Villigen, 5232, Switzerland

    Caroline A. C. Hyde, Philipp Berger & Kurt Ballmer-Hofer

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  1. Caroline A. C. Hyde
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  2. Philipp Berger
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  3. Kurt Ballmer-Hofer
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Correspondence to Kurt Ballmer-Hofer .

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Editors and Affiliations

  1. UMR 1036, Biologie du Cancer et de l’Infection, Institut de Recherches en Technologies et Sciences pour le Vivant, Université Grenoble-Alpes, Grenoble, France

    Jean-Jacques Feige

  2. Institute for Research on Cancer and aging of Nice (IRCAN), University of Nice Sophia Antipolis, Nice, France

    Gilles Pagès

  3. CNRS UMR8161, Institut Pasteur de Lille, Institut de Biologie de Lille, Lille, France

    Fabrice Soncin

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Hyde, C.A.C., Berger, P., Ballmer-Hofer, K. (2014). Finding New Partnerships: The Function of Individual Extracellular Receptor Domains in Angiogenic Signalling by VEGF Receptors. In: Feige, JJ., Pagès, G., Soncin, F. (eds) Molecular Mechanisms of Angiogenesis. Springer, Paris. https://doi.org/10.1007/978-2-8178-0466-8_3

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