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.

scholarly journals PlGF Reduction Compromises Angiogenesis in Diabetic Foot Disease Through Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Lingyan Zhu ◽  
Jieqi Qian ◽  
Yinan Jiang ◽  
Tianlun Yang ◽  
Qiong Duan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Diabetic Foot ◽  
Cell Types ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Adeno Associated Virus ◽  
Diabetic Foot Disease ◽  
Foot Disease ◽  
Endothelial Growth Factor

Diabetic foot disease (DFD) is a common and serious complication for diabetes and is characterized with impaired angiogenesis. In addition to the well-defined role of vascular endothelial growth factor (VEGF) -A and its defect in the pathogenesis of DFD, another VEGF family member, placental growth factor (PlGF), was also recently found to alter expression pattern in the DFD patients with undetermined mechanisms. This question was thus addressed in the current study. We detected attenuated PlGF upregulation in a mouse DFD model. In addition, the major cell types at the wound to express the unique PlGF receptor, VEGF receptor 1 (VEGFR1), were macrophages and endothelial cells. To assess how PlGF regulates DFD-associated angiogenesis, we injected recombinant PlGF and depleted VEGF1R specifically in macrophages by local injection of an adeno-associated virus (AAV) carrying siRNA for VEGFR1 under a macrophage-specific CD68 promoter. We found that the angiogenesis and recovery of the DFD were both improved by PlGF injection. The PlGF-induced improvement in angiogenesis and the recovery of skin injury were largely attenuated by macrophage-specific depletion of VEGF1R, likely resulting from reduced macrophage number and reduced M2 polarization. Together, our data suggest that reduced PlGF compromises angiogenesis in DFD at least partially through macrophages.

scholarly journals Differential Pathways of Angiotensin II-Induced Extracellularly Regulated Kinase 1/2 Phosphorylation in Specific Cell Types: Role of Heparin-Binding Epidermal Growth Factor

2004 ◽  
Vol 18 (8) ◽  
pp. 2035-2048 ◽  
Author(s):  
Bukhtiar H. Shah ◽  
Akin Yesilkaya ◽  
J. Alberto Olivares-Reyes ◽  
Hung-Dar Chen ◽  
László Hunyady ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Types ◽  
Specific Cell ◽  
Heparin Binding ◽  
Epidermal Growth

scholarly journals Regulation of Cell Cycle Progression by Growth Factor-Induced Cell Signaling

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3327
Author(s):  
Zhixiang Wang
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Tyrosine Kinases ◽  
Cell Cycle Progression ◽  
Phase Cell ◽  
Growth Factor Signaling ◽  
Cycle Progression ◽  
M Phase

The cell cycle is the series of events that take place in a cell, which drives it to divide and produce two new daughter cells. The typical cell cycle in eukaryotes is composed of the following phases: G1, S, G2, and M phase. Cell cycle progression is mediated by cyclin-dependent kinases (Cdks) and their regulatory cyclin subunits. However, the driving force of cell cycle progression is growth factor-initiated signaling pathways that control the activity of various Cdk–cyclin complexes. While the mechanism underlying the role of growth factor signaling in G1 phase of cell cycle progression has been largely revealed due to early extensive research, little is known regarding the function and mechanism of growth factor signaling in regulating other phases of the cell cycle, including S, G2, and M phase. In this review, we briefly discuss the process of cell cycle progression through various phases, and we focus on the role of signaling pathways activated by growth factors and their receptor (mostly receptor tyrosine kinases) in regulating cell cycle progression through various phases.

Abstract 1656: Vegf Induces vWF Release via A VEGFR2/Tyr1175-PLC- gamma1 Pathway

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yan Xiong ◽  
Yingqing Huo ◽  
Chao Chen ◽  
Xiaofan Lu ◽  
Jincai Luo
Keyword(s):  
Growth Factor ◽  
Growth Factor Receptor ◽  
Initial Contact ◽  
Vegf Receptor ◽  
Chimeric Receptor ◽  
Vegf Receptors ◽  
Early Passage ◽  
Specific Storage ◽  
C Terminus

Many endothelial inflammatory and prothrombotic mediators are stored in and rapidly released from Weibel-Palade bodies (WPBs), endothelium-specific storage organelles upon stimulation. The von Willebrand factor (vWF), a major component inside WPBs, mediates the initial contact of platelets with the injured vessel wall and thus plays an important role in haemostasis and thrombosis. It has previously been shown that vascular endothelial growth factor (VEGF) triggers a rapid release of vWF. However, specific VEGF receptors and their potential downstream pathways involved in this process have not been carefully determined. To dissect the role of VEGF receptors in vWF release activation, we utilized two approaches: one is to use receptor-specific ligands and the other is to use a chimeric receptor approach. The ligands for VEGF receptor 2 (VEGFR2), but not VEGF receptor 1 (VEGFR1), stimulated vWF release. The predominant role of VEGFR2 in vWF release regulation was further confirmed by using a chimeric receptor approach in which the extracellular domain of the epidermal growth factor receptor was substituted for that of VEGFR1 or VEGFR2, and was then expressed in early-passage HUVECs. Further, the knockdown of phospholipase C-γ1 (PLCγ1) suppressed VEGF-triggered intracellular calcium increase and blocked VEGF-induced vWF release. In addition, the two products of PLCγ1 hydrolysis, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), are both required for VEGF-induced vWF release. Finally, combined with point mutagenesis, the responsible binding sites for PLCγ1 and their importance in VEGFR2-activated vWF release have been determined. Point mutation of a single tyrosine residue Tyr1175, a putative binding site for PLCγ1 on the C-terminus, abolished VEGFR2-activated vWF release. This study presents the first evidence that the PLCγ1 is essential for VEGF-triggered vWF release mediated through a VEGFR2/Tyr1175 pathway.

scholarly journals Transforming growth factor–β in tissue fibrosis

2020 ◽  
Vol 217 (3) ◽  
Author(s):  
Nikolaos G. Frangogiannis
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Cellular Targets ◽  
Extracellular Matrix Molecules ◽  
Interacting Networks

TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

scholarly journals Endothelial-to-Mesenchymal Transition (EndoMT): Roles in Tumorigenesis, Metastatic Extravasation and Therapy Resistance

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Valentin Platel ◽  
Sébastien Faure ◽  
Isabelle Corre ◽  
Nicolas Clere
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Therapy Resistance ◽  
Experimental Conditions ◽  
Potential Implication ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Cancer cells evolve in a very complex tumor microenvironment, composed of several cell types, among which the endothelial cells are the major actors of the tumor angiogenesis. Today, these cells are also characterized for their plasticity, as endothelial cells have demonstrated their potential to modify their phenotype to differentiate into mesenchymal cells through the endothelial-to-mesenchymal transition (EndoMT). This cellular plasticity is mediated by various stimuli including transforming growth factor-β (TGF-β) and is modulated dependently of experimental conditions. Recently, emerging evidences have shown that EndoMT is involved in the development and dissemination of cancer and also in cancer cell to escape from therapeutic treatment. In this review, we summarize current updates on EndoMT and its main induction pathways. In addition, we discuss the role of EndoMT in tumorigenesis, metastasis, and its potential implication in cancer therapy resistance.

VEGF receptor trafficking in angiogenesis

2009 ◽  
Vol 37 (6) ◽  
pp. 1184-1188 ◽  
Author(s):  
Alice Scott ◽  
Harry Mellor
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Intracellular Trafficking ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Signalling Pathways ◽  
Vegf Receptor ◽  
A Cell ◽  
Endosomal Pathway

The intracellular trafficking of receptors provides a way to control the overall sensitivity of a cell to receptor stimulation. These sorting pathways are also used to shape the balance of signals that are generated in response to receptor activation. The major pro-angiogenic growth factor receptor is VEGFR2 (vascular endothelial growth factor 2). VEGFR2 activates a very similar set of signalling pathways to other RTKs (receptor tyrosine kinases); however, its intracellular trafficking is very different. Furthermore, VEGFR2 can form a complex with a range of different angiogenic regulators that in turn regulate the trafficking of VEGFR2 through the endosomal pathway. This regulated trafficking of VEGFR2 has important consequences for angiogenic signalling and is a clear demonstration of how the endosomal pathway plays a critical role in connecting receptor signalling pathways to cellular events.

Redox-dependent MAP kinase signaling by Ang II in vascular smooth muscle cells: role of receptor tyrosine kinase transactivation

2003 ◽  
Vol 81 (2) ◽  
pp. 159-167 ◽  
Author(s):  
Rhian M Touyz ◽  
Montserrat Cruzado ◽  
Fatiha Tabet ◽  
Guoying Yao ◽  
Steven Salomon ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Nadph Oxidase ◽  
Map Kinase ◽  
Vascular Smooth Muscle Cells ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
P38 Map Kinase ◽  
Ang Ii

We investigated the role of receptor tyrosine kinases in Ang II-stimulated generation of reactive oxygen species (ROS) and assessed whether MAP kinase signaling by Ang II is mediated via redox-sensitive pathways. Production of ROS and activation of NADPH oxidase were determined by DCFDA (dichlorodihydrofluorescein diacetate; 2 μmol/L) fluorescence and lucigenin (5 μmol/L) chemiluminescence, respectively, in rat vascular smooth muscle cells (VSMC). Phosphorylation of ERK1/2, p38MAP kinase and ERK5 was determined by immunoblotting. The role of insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) was assessed with the antagonists AG1024 and AG1478, respectively. ROS bioavailability was manipulated with Tiron (10–5 mol/L), an intra cellular scavanger, and diphenylene iodinium (DPI; 10–6 mol/L), an NADPH oxidase inhibitor. Ang II stimulated NADPH oxidase activity and dose-dependently increased ROS production (p < 0.05). These actions were reduced by AG1024 and AG1478. Ang II-induced ERK1/2 phosphorylation (276% of control) was decreased by AG1478 and AG1024. Neither DPI nor tiron influenced Ang II-stimulated ERK1/2 activity. Ang II increased phosphorylation of p38 MAP kinase (204% of control) and ERK5 (278% of control). These effects were reduced by AG1024 and AG1478 and almost abolished by DPI and tiron. Thus Ang II stimulates production of NADPH-inducible ROS partially through transactivation of IGF-1R and EGFR. Inhibition of receptor tyrosine kinases and reduced ROS bioavaliability attenuated Ang II-induced phosphorylation of p38 MAP kinase and ERK5, but not of ERK1/2. These findings suggest that Ang II activates p38MAP kinase and ERK5 via redox-dependent cascades that are regulated by IGF-1R and EGFR transactivation. ERK1/2 regulation by Ang II is via redox-insensitive pathways.Key words: ERK1/2, p38MAP kinase, EGFR, IGF-1R, signal transduction.

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.

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