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Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis

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Abstract

Neuropilins (NRP) play a central role in neuronal and blood vessel development as receptors for two ligand types, the semaphorin (SEMA) family of axon guidance modulators and the VEGF family of angiogenesis stimulators. The role of NRPs in axon guidance is well documented but a role in blood vessel development is less so. NRPs mediate normal developmental angiogenesis as shown in mouse and zebrafish models, and pathological angiogenesis in tumors and retinal disease. The ability of two disparate ligand families to bind to the same receptor is unusual but may be explainable by analysis of neuropilin structure. There are two NRP genes, nrp1 and nrp2. The NRPs have a relatively large extracellular domain consisting of sub domains, which are ligand binding sites. VEGF165 binds to the b1b2 subdomain, SEMA3A and SEMA3F also bind to b1b2 but to a1a2 as well. Mutagenesis studies have identified NRP amino acids that bind VEGF165 but not SEMA3F. These NRP structural elements might dictate differential SEMA and VEGF165 binding properties, which in turn regulate angiogenesis. This article reviews the latest information of NRP structure and how structure influences angiogenesis. In addition, the role of NRPs in human cancer is addressed.

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Fig. 1

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Abbreviations

NRP:

Neuropilin

SEMA:

Semaphorin

VEGF:

Vascular endothelial growth factor

VEGFR:

VEGF receptor

EC:

Endothelial cell

ISV:

Intersegmental vessels

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Acknowledgments

We thank Melissa Herman for proofreading the manuscript and Kristin Johnson for technical assistance in figure preparation. This work was supported by National Institute of Health NCI grants CA37392 and CA45548 (to M.K.).

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Authors and Affiliations

  1. Department of Surgery, Vascular Biology Program, Children’s Hospital and Harvard Medical School, Karp Building 12210, 300 Longwood Ave., Boston, MA, 02115, USA

    Elena Geretti, Akio Shimizu & Michael Klagsbrun

  2. Department of Pathology, Vascular Biology Program, Children’s Hospital and Harvard Medical School, Karp Building 12210, 300 Longwood Ave., Boston, MA, 02115, USA

    Michael Klagsbrun

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  1. Elena Geretti
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  2. Akio Shimizu
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  3. Michael Klagsbrun
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Correspondence to Michael Klagsbrun.

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We dedicate this article to the memory of Dr. Judah Folkman, the leading pioneer of angiogenesis research.

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Geretti, E., Shimizu, A. & Klagsbrun, M. Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis. Angiogenesis 11, 31–39 (2008). https://doi.org/10.1007/s10456-008-9097-1

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