Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 816-826 ◽  
Author(s):  
Kurt Ballmer-Hofer ◽  
Anneli E. Andersson ◽  
Laura E. Ratcliffe ◽  
Philipp Berger
Keyword(s):  
Tyrosine Kinases ◽  
Lymph Vessel ◽  
General Mechanism ◽  
Binding Motif ◽  
Vascular Endothelial ◽  
Neuropilin 1 ◽  
Signal Output ◽  
Vessel Development ◽  
Endothelial Growth Factors

Abstract Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development by activating 3 receptor tyrosine kinases (RTKs), VEGFR-1, -2, and -3, and by binding to coreceptors such as neuropilin-1 (NRP-1). We investigated how different VEGF-A isoforms, in particular VEGF-A165a and VEGF-A165b, control the balance between VEGFR-2 recycling, degradation, and signaling. Stimulation of cells with the NRP-1–binding VEGF-A165a led to sequential NRP-1–mediated VEGFR-2 recycling through Rab5, Rab4, and Rab11 vesicles. Recycling was accompanied by dephosphorylation of VEGFR-2 between Rab4 and Rab11 vesicles and quantitatively and qualitatively altered signal output. In cells stimulated with VEGF-A165b, an isoform unable to bind NRP-1, VEGFR-2 bypassed Rab11 vesicles and was routed to the degradative pathway specified by Rab7 vesicles. Deletion of the GIPC (synectin) binding motif of NRP-1 prevented transition of VEGFR-2 through Rab11 vesicles and attenuated signaling. Coreceptor engagement was specific for VEGFR-2 because EGFR recycled through Rab11 vesicles in the absence of known coreceptors. Our data establish a distinct role of NRP-1 in VEGFR-2 signaling and reveal a general mechanism for the function of coreceptors in modulating RTK signal output.

Neuropilin signalling in angiogenesis

2012 ◽  
Vol 40 (1) ◽  
pp. 20-25 ◽  
Author(s):  
Sina Koch
Keyword(s):  
Tyrosine Kinases ◽  
Lymphatic Vessel ◽  
Tissue Growth ◽  
Vascular Endothelial Growth Factors ◽  
Vascular Endothelial ◽  
Blood Vessel Formation ◽  
Master Regulators ◽  
Receptor Signalling ◽  
Health And Disease ◽  
Endothelial Growth Factors

VEGFs (vascular endothelial growth factors) are master regulators of vascular development and of blood and lymphatic vessel function during health and disease in adults. This family of five mammalian ligands acts through three RTKs (receptor tyrosine kinases). In addition, co-receptors such as NRPs (neuropilins) associate with the ligand–receptor signalling complex and modulate the output. Therapeutics to block several of the VEGF signalling components as well as NRP function have been developed with the aim of halting blood vessel formation, angiogenesis, in diseases that involve tissue growth and inflammation, such as cancer. The present review outlines the current understanding of NRPs in relation to blood and lymphatic vessel biology.

scholarly journals Role of hypoxia and vascular endothelial growth factors in lymphangiogenesis

2014 ◽  
Vol 1 (1) ◽  
pp. e29907 ◽  
Author(s):  
Florent Morfoisse ◽  
Edith Renaud ◽  
Fransky Hantelys ◽  
Anne-Catherine Prats ◽  
Barbara Garmy-Susini
Keyword(s):  
Growth Factors ◽  
Vascular Endothelial Growth Factors ◽  
Vascular Endothelial ◽  
Endothelial Growth Factors

scholarly journals The Role of Rho GTPases in VEGF Signaling in Cancer Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Nada El Baba ◽  
Mohammad Farran ◽  
Elie Abi Khalil ◽  
Leila Jaafar ◽  
Isabelle Fakhoury ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Rho Gtpases ◽  
Intracellular Signaling ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Transmembrane Receptors ◽  
Vegf Signaling ◽  
Endothelial Growth Factors

Vascular endothelial growth factors (VEGFs) consist of five molecules (VEGFA through D as well as placental growth factor) which are crucial for regulating key cellular and tissue functions. The role of VEGF and its intracellular signaling and downstream molecular pathways have been thoroughly studied. Activation of VEGF signal transduction can be initiated by the molecules’ binding to two classes of transmembrane receptors: (1) the VEGF tyrosine kinase receptors (VEGF receptors 1 through 3) and (2) the neuropilins (NRP1 and 2). The involvement of Rho GTPases in modulating VEGFA signaling in both cancer cells and endothelial cells has also been well established. Additionally, different isoforms of Rho GTPases, namely, RhoA, RhoC, and RhoG, have been shown to regulate VEGF expression as well as blood vessel formation. This review article will explore how Rho GTPases modulate VEGF signaling and the consequences of such interaction on cancer progression.

scholarly journals Role of hypoxia and vascular endothelial growth factors in lymphangiogenesis

2015 ◽  
Vol 2 (4) ◽  
pp. e1024821 ◽  
Author(s):  
Florent Morfoisse ◽  
Edith Renaud ◽  
Fransky Hantelys ◽  
Anne-Catherine Prats ◽  
Barbara Garmy-Susini
Keyword(s):  
Growth Factors ◽  
Vascular Endothelial Growth Factors ◽  
Vascular Endothelial ◽  
Endothelial Growth Factors

Differential Expression of VEGF Receptors on Human T Cell Subsets

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4906-4906
Author(s):  
Stephen A Lee ◽  
Nichole L Corless ◽  
Dean A. Lee
Keyword(s):  
Differential Expression ◽  
Tissue Growth ◽  
T Cell Subsets ◽  
Vascular Endothelial ◽  
Vegf Receptors ◽  
Rt Pcr ◽  
Splice Isoforms ◽  
Human T Cell ◽  
Neuropilin 1 ◽  
Endothelial Growth Factors

Abstract Vascular endothelial growth factors (VEGF) and their receptors (VEGFR) deliver important signals that controlling the angiogenesis of growing, injured, and malignant tissues. Expression of VEGF receptors has been described on a variety of normal and malignant leukocytes, and presumably plays a role in their trafficking to injured tissue. Differential expression of neuropilin-1 (NRP-1) has been described as a marker of regulatory T cells (Treg) in mice, and may be expressed on human thymocytes, but expression on human Tregs has not been confirmed. Moreover, earlier reports of Treg-specific markers in humans were based on the CD4+CD25+ subset, which is not as reliable for Treg identification as it is in mice. We used cell sorting to obtain pure populations of human Tregs (using the more stringent criteria of CD4+CD25+CD125−) and T helper cells (Th) (CD4+CD25−CD127+). We compared expression in these subsets of VEGFR-1, -2, -3, and NRP-1 and -2 using flow cytometry and quantitative RT-PCR, and NRP-1 splice isoforms by RT-PCR using isoform-specific primers. We were not able to identify any NRP-1 expression in Tregs by any of these methods. In contrast, there was marked differential expression of VEGFR-2 (Flk-1) and -3 (Flt-4), both of which exhibited up to 16-fold higher expression in Tregs than in Th. These findings suggest a role for VEGF in recruiting Tregs to sites of tissue growth as a mechanism for blunting potential autoimmunity to neoexpressed antigens, and thus may also explain the accumulation of Tregs in tumors.

scholarly journals Phytochemicals Targeting VEGF and VEGF-Related Multifactors as Anticancer Therapy

2019 ◽  
Vol 8 (3) ◽  
pp. 350 ◽  
Author(s):  
Amna Parveen ◽  
Lalita Subedi ◽  
Heung Kim ◽  
Zahra Khan ◽  
Zahra Zahra ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Anticancer Therapy ◽  
Cancer Growth ◽  
Vascular Endothelial ◽  
Vegf Signaling ◽  
Multiple Factors ◽  
Cancer Initiation ◽  
Bioactive Phytochemicals ◽  
Endothelial Growth Factor

The role of vascular endothelial growth factor (VEGF) in cancer cells is not limited to angiogenesis; there are also multiple factors, such as neuropilins (non-tyrosine kinases receptors), tyrosine kinases receptors, immunodeficiencies, and integrins, that interact with VEGF signaling and cause cancer initiation. By combating these factors, tumor progression can be inhibited or limited. Natural products are sources of several bioactive phytochemicals that can interact with VEGF-promoting factors and inhibit them through various signaling pathways, thereby inhibiting cancer growth. This review provides a deeper understanding of the relation and interaction of VEGF with cancer-promoting factors and phytochemicals in order to develop multi-targeted cancer prevention and treatment.

Crotalid venom vascular endothelial growth factors has preferential affinity for VEGFR-1

2005 ◽  
Vol 93 (02) ◽  
pp. 331-338 ◽  
Author(s):  
Yuh-Ling Chen ◽  
Tse-Ming Hong ◽  
Shu-Huei Tsai ◽  
Inn-Ho Tsai
Keyword(s):  
Tissue Factor ◽  
Chorioallantoic Membrane ◽  
Human Monocyte ◽  
Venom Gland ◽  
Vascular Endothelial ◽  
Amino Acid Residues ◽  
Factor Production ◽  
Neuropilin 1 ◽  
Monocyte Chemotaxis ◽  
Endothelial Growth Factors

SummaryPm-VEGF, a novel member ofVEGF family from the venom gland of Taiwan habu (Protobothrops mucrosquamatu), is a disulfidelinked homodimer with 119 amino acid residues. Recombinant fusion Pm-VEGF was expressed in Escherichia coli, purified and refolded. Surface plasmon resonance was used to determine its binding kinetics toVEGF-receptors (VEGFR). Relative to human VEGF165, the binding affinity of Pm-VEGF to the VEGFR-1 was 1.7-fold higher while affinity to the VEGFR-2 was 17-fold lower. But it did not bind theVEGFR-3 or neuropilin-1. Pm-VEGF promoted the proliferation and tissue factor production of endothelial cells, the neovascularization in the chicken chorioallantoic membrane, and increased vascular permeability. It also stimulated tissue-factor production and human monocyte chemotaxis, in accord with its specificity for VEGFR-1. Structural comparison among VEGF-proteins from various viper venoms revealed that the two subfamilies of vipers (Crotalinae and Viperinae) have evolved with distinct receptor-specificities for VEGFR-1 and VEGFR-2, respectively. Discussion on structureactivity relationships of the VEGFs further provided insight into residues important for the receptor-binding and specificities.

How neuropilin-1 regulates receptor tyrosine kinase signalling: the knowns and known unknowns

2011 ◽  
Vol 39 (6) ◽  
pp. 1583-1591 ◽  
Author(s):  
Ian C. Zachary
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Cell Types ◽  
Vegf Receptor ◽  
Cardiovascular Development ◽  
Axon Targeting ◽  
Neuropilin 1 ◽  
Known Unknowns ◽  
Basic Features

Essential roles of NRP1 (neuropilin-1) in cardiovascular development and in neuronal axon targeting during embryogenesis are thought to be mediated primarily through binding of NRP1 to two unrelated types of ligands: the VEGF (vascular endothelial growth factor) family of angiogenic cytokines in the endothelium, and the class 3 semaphorins in neurons. A widely accepted mechanism for the role of NRP1 in the endothelium is VEGF binding to NRP1 and VEGFR2 (VEGF receptor 2) and VEGF-dependent formation of complexes or NRP1–VEGFR2 holoreceptors with enhanced signalling activity and biological function. However, although some basic features of this model are solidly based on biochemical and cellular data, others are open to question. Furthermore, a mechanistic account of NRP1 has to accommodate research which emphasizes the diversity of NRP1 functions in different cell types and particularly an emerging role in signalling by other growth factor ligands for RTKs (receptor tyrosine kinases) such as HGF (hepatocyte growth factor) and PDGF (platelet-derived growth factor). It is uncertain, however, whether the model of NRP1–RTK heterocomplex formation applies in all of these situations. In the light of these developments, the need to explain mechanistically the role of NRP1 in signalling is coming increasingly to the fore. The present article focuses on some of the most important unresolved questions concerning the mechanism(s) through which NRP1 acts, and highlights recent findings which are beginning to generate insights into these questions.

Sign in / Sign up

Export Citation Format

Share Document