Neuropilins in the Context of Tumor Vasculature

Neuropilin-1 and Neuropilin-2 form a small family of plasma membrane spanning receptors originally identified by the binding of semaphorin and vascular endothelial growth factor. Having no cytosolic protein kinase domain, they function predominantly as co-receptors of other receptors for various ligands. As such, they critically modulate the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. This review highlights the diverse neuropilin ligands and interacting partners on endothelial cells, which are relevant in the context of the tumor vasculature and the tumor microenvironment. In addition to tumor cells, the latter contains cancer-associated fibroblasts, immune cells, and endothelial cells. Based on the prevalent neuropilin-mediated interactions, the suitability of various neuropilin-targeted substances for influencing tumor angiogenesis as a possible building block of a tumor therapy is discussed.

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Co-expression of vascular endothelial growth factor and neuropilin-1 in ovine feto-placental artery endothelial cells

Molecular and Cellular Endocrinology ◽

10.1016/s0303-7207(02)00190-9 ◽

2002 ◽

Vol 196 (1-2) ◽

pp. 95-106 ◽

Cited By ~ 16

Author(s):

Stephen C.M Tsoi ◽

YunXia Wen ◽

Jin-Young Chung ◽

DongBao Chen ◽

Ronald R Magness ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Vascular Endothelial ◽

Neuropilin 1 ◽

Endothelial Growth Factor

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Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelial growth factor receptor-2

Blood ◽

10.1182/blood-2004-07-2598 ◽

2005 ◽

Vol 105 (5) ◽

pp. 1992-1999 ◽

Cited By ~ 83

Author(s):

Matilde Murga ◽

Oscar Fernandez-Capetillo ◽

Giovanna Tosato

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Endothelial Cell ◽

Growth Factor ◽

Critical Role ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Human Endothelial Cells ◽

Neuropilin 1 ◽

Endothelial Growth Factor

AbstractNeuropilin-1 (NRP-1) is a type 1 membrane protein that binds the axon guidance factors belonging to the class-3 semaforin family. In endothelial cells, NRP-1 serves as a co-receptor for vascular endothelial growth factor (VEGF) and regulates VEGF receptor 2 (VEGFR-2)–dependent angiogenesis. Although gene-targeting studies documenting embryonic lethality in NRP-1 null mice have demonstrated a critical role for NRP-1 in vascular development, the activities of NRP-1 in mature endothelial cells have been incompletely defined. Using RNA interference-mediated silencing of NRP-1 or VEGFR-2 in primary human endothelial cells, we confirm that NRP-1 modulates VEGFR-2 signaling-dependent mitogenic functions of VEGF. Importantly, we now show that NRP-1 regulates endothelial cell adhesion to extracellular matrix proteins independently of VEGFR-2. Based on its dual role as an enhancer of VEGF activity and a mediator of endothelial cell adhesiveness described here, NRP-1 emerges as a promising molecular target for the development of antiangiogenic drugs.

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R-Ras Protein Inhibits Autophosphorylation of Vascular Endothelial Growth Factor Receptor 2 in Endothelial Cells and Suppresses Receptor Activation in Tumor Vasculature

Journal of Biological Chemistry ◽

10.1074/jbc.m114.591511 ◽

2015 ◽

Vol 290 (13) ◽

pp. 8133-8145 ◽

Cited By ~ 14

Author(s):

Junko Sawada ◽

Fangfei Li ◽

Masanobu Komatsu

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Growth Factor Receptor ◽

Tumor Vasculature ◽

Receptor Activation ◽

Vascular Endothelial ◽

Ras Protein ◽

Endothelial Growth Factor

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Neuropilin-1 in regulation of VEGF-induced activation of p38MAPK and endothelial cell organization

Blood ◽

10.1182/blood-2007-12-125856 ◽

2008 ◽

Vol 112 (9) ◽

pp. 3638-3649 ◽

Cited By ~ 109

Author(s):

Harukiyo Kawamura ◽

Xiujuan Li ◽

Katsutoshi Goishi ◽

Laurens A. van Meeteren ◽

Lars Jakobsson ◽

...

Keyword(s):

Endothelial Cells ◽

Embryonic Stem ◽

Embryoid Bodies ◽

Vascular Endothelial ◽

Loss Of Function ◽

Sprouting Angiogenesis ◽

Neuropilin 1 ◽

Cell Organization ◽

Vascular Structures ◽

Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF)–A regulates vascular development and angiogenesis. VEGF isoforms differ in ability to bind coreceptors heparan sulfate (HS) and neuropilin-1 (NRP1). We used VEGF-A165 (which binds HS and NRP1), VEGF-A121 (binds neither HS nor NRP1), and parapoxvirus VEGF-E-NZ2 (binds NRP1 but not HS) to investigate the role of NRP1 in organization of endothelial cells into vascular structures. All 3 ligands induced similar level of VEGFR-2 tyrosine phosphorylation in the presence of NRP1. In contrast, sprouting angiogenesis in differentiating embryonic stem cells (embryoid bodies), formation of branching pericyte-embedded vessels in subcutaneous matrigel plugs, and sprouting of intersegmental vessels in developing zebrafish were induced by VEGF-A165 and VEGF-E-NZ2 but not by VEGF-A121. Analyses of recombinant factors with NRP1-binding gain- and loss-of-function properties supported the conclusion that NRP1 is critical for VEGF-induced sprouting and branching of endothelial cells. Signal transduction antibody arrays implicated NRP1 in VEGF-induced activation of p38MAPK. Inclusion of the p38MAPK inhibitor SB203580 in VEGF-A165–containing matrigel plugs led to attenuated angiogenesis and poor association with pericytes. Our data strongly indicate that the ability of VEGF ligands to bind NRP1 influences p38MAPK activation, and formation of functional, pericyte-associated vessels.

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VEGF regulates the mobilization of VEGFR2/KDR from an intracellular endothelial storage compartment

Blood ◽

10.1182/blood-2005-12-007484 ◽

2006 ◽

Vol 108 (8) ◽

pp. 2624-2631 ◽

Cited By ~ 120

Author(s):

Alexandra Gampel ◽

Lara Moss ◽

Matt C. Jones ◽

Val Brunton ◽

Jim C. Norman ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Tyrosine Kinases ◽

Intracellular Trafficking ◽

Receptor Tyrosine Kinases ◽

Significant Proportion ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Src Tyrosine Kinase ◽

Endothelial Growth Factor

AbstractEndothelial cells respond to vascular endothelial growth factor (VEGF) to produce new blood vessels. This process of angiogenesis makes a critical contribution during embryogenesis and also in the response to ischemia in adult tissues. We have studied the intracellular trafficking of the major VEGF receptor KDR (VEGFR2). Unlike other related growth factor receptors, we find that a significant proportion of KDR is held in an endosomal storage pool within endothelial cells. We find that KDR can be delivered to the plasma membrane from this intracellular pool and that VEGF stimulates this recycling to the cell surface. KDR recycling appears to be distinct from the previously characterized Rab4- and Rab11-dependent pathways, but, instead, KDR+ recycling vesicles contain Src tyrosine kinase and VEGF-stimulated recycling requires Src activation. Taken together, these data show that intracellular trafficking of KDR is markedly different from other receptor tyrosine kinases and suggest that the regulation of KDR trafficking by VEGF provides a novel mechanism for controlling the sensitivity of endothelial cells to proangiogenic signals.

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Detection and Quantification of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases in Primary Human Endothelial Cells

Methods in Molecular Biology - VEGF Signaling ◽

10.1007/978-1-4939-2917-7_4 ◽

2015 ◽

pp. 49-65 ◽

Cited By ~ 1

Author(s):

Gareth W. Fearnley ◽

Stephen B. Wheatcroft ◽

Sreenivasan Ponnambalam

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Growth Factor Receptor ◽

Vascular Endothelial ◽

Human Endothelial Cells ◽

Endothelial Growth Factor ◽

Detection And Quantification

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Bmx Tyrosine Kinase Has a Redundant Function Downstream of Angiopoietin and Vascular Endothelial Growth Factor Receptors in Arterial Endothelium

Molecular and Cellular Biology ◽

10.1128/mcb.21.14.4647-4655.2001 ◽

2001 ◽

Vol 21 (14) ◽

pp. 4647-4655 ◽

Cited By ~ 48

Author(s):

Iiro Rajantie ◽

Niklas Ekman ◽

Kristiina Iljin ◽

Elena Arighi ◽

Yuji Gunji ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Tyrosine Kinase ◽

Tyrosine Kinases ◽

Growth Factor Receptors ◽

Vascular Endothelial ◽

Kinase Gene ◽

Venae Cavae ◽

Endothelial Growth Factor

ABSTRACT The Bmx gene, a member of the Tec tyrosine kinase gene family, is known to be expressed in subsets of hematopoietic and endothelial cells. In this study, mice were generated in which the first coding exon of the Bmx gene was replaced with thelacZ reporter gene by a knock-in strategy. The homozygous mice lacking Bmx activity were fertile and had a normal life span without an obvious phenotype. Staining of their tissues using β-galactosidase substrate to assess the sites ofBmx expression revealed strong signals in the endothelial cells of large arteries and in the endocardium starting between days 10.5 and 12.5 of embryogenesis and continuing in adult mice, while the venular endothelium showed a weak signal only in the superior and inferior venae cavae. Of the five known endothelial receptor tyrosine kinases tested, activated Tie-2 induced tyrosyl phosphorylation of the Bmx protein and both Tie-2 and vascular endothelial growth factor receptor 1 (VEGFR-1) stimulated Bmx tyrosine kinase activity. Thus, the Bmx tyrosine kinase has a redundant role in arterial endothelial signal transduction downstream of the Tie-2 and VEGFR-1 growth factor receptors.

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Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.95.16.9349 ◽

1998 ◽

Vol 95 (16) ◽

pp. 9349-9354 ◽

Cited By ~ 706

Author(s):

Sachie Hiratsuka ◽

Osamu Minowa ◽

Junko Kuno ◽

Tetsuo Noda ◽

Masabumi Shibuya

Keyword(s):

Embryonic Development ◽

Tyrosine Kinase ◽

Ligand Binding ◽

Tyrosine Kinases ◽

Kinase Domain ◽

Biological Role ◽

Tyrosine Kinase Domain ◽

Vascular Endothelial ◽

Null Mutant Mice ◽

Endothelial Growth Factor

Receptor tyrosine kinases Flt-1 and Flk-1/KDR, and their ligand, the vascular endothelial growth factor (VEGF), were shown to be essential for angiogenesis in the mouse embryo by gene targeting. Flk-1/KDR null mutant mice exhibited impaired endothelial and hematopoietic cell development. On the other hand, Flt-1 null mutation resulted in early embryonic death at embryonic day 8.5, showing disorganization of blood vessels, such as overgrowth of endothelial cells. Flt-1 differs from Flk-1 in that it displays a higher affinity for VEGF but lower kinase activity, suggesting the importance of its extracellular domain. To examine the biological role of Flt-1 in embryonic development and vascular formation, we deleted the kinase domain without affecting the ligand binding region. Flt-1 tyrosine kinase-deficient homozygous mice (flt-1TK−/−) developed normal vessels and survived. However, VEGF-induced macrophage migration was strongly suppressed inflt-1TK−/−mice. These results indicate that Flt-1 without tyrosine kinase domain is sufficient to allow embryonic development with normal angiogenesis, and that a receptor tyrosine kinase plays a main biological role as a ligand-binding molecule.

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