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.

Epithelial Fibroblast Growth Factor Receptor 1 Regulates Enamel Formation

2008 ◽  
Vol 87 (3) ◽  
pp. 238-243 ◽  
Author(s):  
K. Takamori ◽  
R. Hosokawa ◽  
X. Xu ◽  
X. Deng ◽  
P. Bringas ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Tooth Development ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Fgf Signaling ◽  
Enamel Formation ◽  
Enamel Structure ◽  
A Cell

The interaction between epithelial and mesenchymal tissues plays a critical role in the development of organs such as teeth, lungs, and hair. During tooth development, fibroblast growth factor (FGF) signaling is critical for regulating reciprocal epithelial and mesenchymal interactions. FGF signaling requires FGF ligands and their receptors (FGFRs). In this study, we investigated the role of epithelial FGF signaling in tooth development, using the Cre-loxp system to create tissue-specific inactivation of Fgfr1 in mice. In K14-Cre;Fgfr1 fl/fl mice, the apical sides of enamel-secreting ameloblasts failed to adhere properly to each other, although ameloblast differentiation was unaffected at early stages. Prior to eruption, enamel structure was compromised in the K14-Cre;Fgfr1 fl/fl mice and displayed severe enamel defects that mimic amelogenesis imperfecta (AI), with a rough, irregular enamel surface. These results suggest that there is a cell-autonomous requirement for FGF signaling in the dental epithelium during enamel formation. Loss of Fgfr1 affects ameloblast organization at the enamel-secretory stage and, hence, the formation of enamel.

scholarly journals Grb10, a Positive, Stimulatory Signaling Adapter in Platelet-Derived Growth Factor BB-, Insulin-Like Growth Factor I-, and Insulin-Mediated Mitogenesis

1999 ◽  
Vol 19 (9) ◽  
pp. 6217-6228 ◽  
Author(s):  
Jian Wang ◽  
Heping Dai ◽  
Nasim Yousaf ◽  
Mustapha Moussaif ◽  
Youping Deng ◽  
...  
Keyword(s):  
Growth Factor ◽  
Dna Synthesis ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Sh2 Domain ◽  
Fusion Peptides ◽  
Binding Region ◽  
Igf I ◽  
A Cell ◽  
Experimental Strategies

ABSTRACT Grb10 has been described as a cellular partner of several receptor tyrosine kinases, including the insulin receptor (IR) and the insulin-like growth factor I (IGF-I) receptor (IGF-IR). Its cellular role is still unclear and a positive as well as an inhibitory role in mitogenesis depending on the cell context has been implicated. We have tested other mitogenic receptor tyrosine kinases as putative Grb10 partners and have identified the activated forms of platelet-derived growth factor (PDGF) receptor β (PDGFRβ), hepatocyte growth factor receptor (Met), and fibroblast growth factor receptor as candidates. We have mapped Y771 as a PDFGRβ site that is involved in the association with Grb10 via its SH2 domain. We have further investigated the putative role of Grb10 in mitogenesis with four independent experimental strategies and found that all consistently suggested a role as a positive, stimulatory signaling adaptor in normal fibroblasts. (i) Complete Grb10 expression from cDNA with an ecdysone-regulated transient expression system stimulated PDGF-BB-, IGF-I, and insulin- but not epidermal growth factor (EGF)-induced DNA synthesis in an ecdysone dose-responsive fashion. (ii) Microinjection of the (dominant-negative) Grb10 SH2 domain interfered with PDGF-BB- and insulin-induced DNA synthesis. (iii) Alternative experiments were based on cell-permeable fusion peptides with the Drosophilaantennapedia homeodomain which effectively traverse the plasma membrane of cultured cells. A cell-permeable Grb10 SH2 domain similarly interfered with PDGF-BB-, IGF-I-, and insulin-induced DNA synthesis. In contrast, a cell-permeable Grb10 Pro-rich putative SH3 domain binding region interfered with IGF-I- and insulin- but not with PDGF-BB- or EGF-induced DNA synthesis. (iv) Transient overexpression of complete Grb10 increased whereas cell-permeable Grb10 SH2 domain fusion peptides substantially decreased the cell proliferation rate (as measured by cell numbers) in normal fibroblasts. These experimental strategies independently suggest that Grb10 functions as a positive, stimulatory, mitogenic signaling adapter in PDGF-BB, IGF-I, and insulin action. This function appears to involve the Grb10 SH2 domain, a novel sequence termed BPS, and the Pro-rich putative SH3 domain binding region in IGF-I- and insulin-mediated mitogenesis. In contrast, PDGF-BB-mediated mitogenesis appears to depend on the SH2 but not on the Pro-rich region and may involve other, unidentified Grb10 domains. Distinct protein domains may help to define specific Grb10 functions in different signaling pathways.

scholarly journals Antagonism between EGFR and Wingless signalling in the larval cuticle of Drosophila

Development ◽  
1997 ◽  
Vol 124 (16) ◽  
pp. 3209-3219 ◽  
Author(s):  
D. Szuts ◽  
M. Freeman ◽  
M. Bienz
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Dominant Negative ◽  
Signalling Pathways ◽  
Embryonic Cells ◽  
Larval Cuticle ◽  
Epidermal Growth

Signalling by the epidermal growth factor receptor (EGFR) plays a critical role in the segmental patterning of the ventral larval cuticle in Drosophila: by expressing a dominant-negative EGFR molecule or Spitz, an activating ligand of EGFR, we show that EGFR signalling specifies the anterior denticles in each segment of the larval abdomen. We provide evidence that these denticles derive from a segmental zone of embryonic cells in which EGFR signalling activity is maximal. Within each segment, there is a competition between the denticle fate specified by EGFR signalling and the naked cuticle fate specified by Wingless signalling. The final pattern of the denticle belts is the product of this antagonism between the two signalling pathways. Finally, we show that the segmental zones of high EGFR signalling activity depend on bithorax gene function and that they account for the main difference in shape between abdominal and thoracic denticle belts.

Phase I trial of PTK787/ZK222584 (PTK/ZK) in combination with carboplatin (C) and paclitaxel (T) in platinum-sensitive recurrent epithelial ovarian (EOC), fallopian tube (FT), or primary peritoneal (PPC) cancers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5564-5564 ◽  
Author(s):  
M. M. Juretzka ◽  
C. Aghajanian ◽  
M. L. Hensley ◽  
W. P. Tew ◽  
D. Spriggs ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase I ◽  
Tyrosine Kinases ◽  
Angiogenesis Inhibitor ◽  
Growth Factor Receptor ◽  
Liver Function Tests ◽  
Maximum Tolerated Dose ◽  
Vegf Receptor ◽  
Open Label ◽  
Platinum Sensitive

5564 Background: Targeting vascular endothelial growth factor (VEGF) in patients (pts) with ovarian cancer achieves objective responses. PTK/ZK is an orally active angiogenesis inhibitor which blocks all known VEGF receptor and platelet-derived growth factor receptor tyrosine kinases. A previous study administered PTK/ZK only on days 3–21 of C and T cycle based on pre-clinical data suggesting PTK/ZK increases T levels (PROC ASCO # 5042, 2005), and recent data supports bid dosing (JCO 18:1–10, 2005). Methods: In this open label, single institution phase I study, pts with platinum sensitive recurrent EOC, FT, or PPC were treated with C and T every 21 days with increasing continuous daily doses of PTK/ZK (250 mg to 1,250mg with bid dosing). Primary endpoints were safety and maximum tolerated dose (MTD). Pharmacokinetic (PK) analysis is planned to describe C and T pharmacokinetics when combined with PTK/ZK. Results: To date, 14 pts with median age 61 (range 45–73) have been enrolled on the first 3 dose levels, including 13 EOC and 1 PPC. All patients were evaluable for toxicity and 8 were evaluable for investigator assessed response. MTD has not been reached. Febrile neutropenia was dose limiting toxicity requiring expansion at levels II and III. PK analysis is ongoing. To date, best responses are: 4 (PR), 3 (SD) and 1 (POD). Other G III toxicity included: C hypersensitivity reaction (1, gr 3), hyperglycemia (4, gr 3), hypertension (1, gr 3), diarrhea (1, gr 3), and elevated liver function tests (1, gr 3). Conclusion: PTK/ZK can be administered continuously in combination with standard doses of C and T using bid dosing. MTD is not yet reached and accrual is ongoing. PK data and MTD will be presented. Supported by Novartis and Bayer Schering Pharma. [Table: see text] No significant financial relationships to disclose.

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

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2624-2631 ◽  
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.

scholarly journals Distinct Mechanisms of Activation of Stat1 and Stat3 by Platelet-Derived Growth Factor Receptor in a Cell-Free System

1999 ◽  
Vol 19 (5) ◽  
pp. 3727-3735 ◽  
Author(s):  
Marie-Luce Vignais ◽  
Michael Gilman
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Membrane Fraction ◽  
Growth Factor Receptor ◽  
Direct Interaction ◽  
Platelet Derived Growth Factor ◽  
Cytosolic Fraction ◽  
Free System ◽  
Cell Free System ◽  
A Cell

ABSTRACT Ligand-dependent activation of the platelet-derived growth factor receptor (PDGFR) in fibroblasts in culture leads to the activation of the JAK family of protein-tyrosine kinases and of the transcription factors Stat1 and Stat3. To determine the biochemical mechanism of STAT activation by PDGFR, we devised a cell-free system composed of a membrane fraction from cells overexpressing PDGFR. When supplemented with crude cytosol, the membrane fraction supported PDGF- and ATP-dependent activation of both Stat1 and Stat3. However, the extent of Stat3 activation differed depending on the source of the cytosolic fraction. Using purified recombinant STAT proteins produced inEscherichia coli, we found that Stat1 could be activated by immunopurified PDGFR and showed no additional requirement for membrane- or cytosol-derived proteins. In contrast, activation of Stat3 exhibited a strong requirement for the cytosolic fraction. The activity present in the cytosolic fraction could be depleted with antibodies to JAK proteins. We conclude that the mechanisms of activation of Stat1 and Stat3 by PDGFR are distinct. Stat1 activation appears to result from a direct interaction with the receptor, whereas Stat3 activation additionally requires JAK proteins.

scholarly journals Receptor Tyrosine Kinases and Inhibitors in Lung Cancer

2004 ◽  
Vol 4 ◽  
pp. 589-604 ◽  
Author(s):  
Evan Pisick ◽  
Simha Jagadeesh ◽  
Ravi Salgia
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Cell Carcinoma ◽  
Small Cell Carcinoma ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Vegf Receptor ◽  
Lung Cancers

Lung cancer is a deadly disease with high mortality and morbidity. Most cases of lung cancer are due to non-small cell carcinoma, with 16% of cases being small cell carcinoma. The biology at a cellular level is of interest at many levels. Knowing cellular pathways helps to further enhance our knowledge of how lung cancer cells survive, proliferate, and metastasize. The receptor tyrosine kinases (RTKs) located at the cellular membrane are becoming of great interest as sites for targeted therapies for lung cancers. This review will discuss the RTKs that are involved in lung cancers and the newer therapies that are being tested. We will specifically discuss receptors such as epidermal growth factor receptor, c-Kit receptor, VEGF receptor, c-Met receptor, insulin growth factor receptor, and Eph receptor. The inhibitors against the specific RTKs are in various preclinical and clinical trials, and this will be detailed.

scholarly journals Structural Basis for Vascular Endothelial Growth Factor Receptor Activation and Implications for Disease Therapy

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1673
Author(s):  
Faheem Shaik ◽  
Gary Cuthbert ◽  
Shervanthi Homer-Vanniasinkam ◽  
Stephen Muench ◽  
Sreenivasan Ponnambalam ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Current Knowledge ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Membrane Receptors ◽  
Structural Basis ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Diverse Range

Vascular endothelial growth factors (VEGFs) bind to membrane receptors on a wide variety of cells to regulate diverse biological responses. The VEGF-A family member promotes vasculogenesis and angiogenesis, processes which are essential for vascular development and physiology. As angiogenesis can be subverted in many disease states, including tumour development and progression, there is much interest in understanding the mechanistic basis for how VEGF-A regulates cell and tissue function. VEGF-A binds with high affinity to two VEGF receptor tyrosine kinases (VEGFR1, VEGFR2) and with lower affinity to co-receptors called neuropilin-1 and neuropilin-2 (NRP1, NRP2). Here, we use a structural viewpoint to summarise our current knowledge of VEGF-VEGFR activation and signal transduction. As targeting VEGF-VEGFR activation holds much therapeutic promise, we examine the structural basis for anti-angiogenic therapy using small-molecule compounds such as tyrosine kinase inhibitors that block VEGFR activation and downstream signalling. This review provides a rational basis towards reconciling VEGF and VEGFR structure and function in developing new therapeutics for a diverse range of ailments.

Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery

2020 ◽  
Vol 17 (5) ◽  
pp. 585-615 ◽  
Author(s):  
Nikhil S. Sakle ◽  
Shweta A. More ◽  
Sachin A. Dhawale ◽  
Santosh N. Mokale
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Small Molecule ◽  
Anaplastic Lymphoma Kinase ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Myelogenous Leukemia ◽  
Cell Functions ◽  
Anaplastic Lymphoma

Background: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells. Methods: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets. Results: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention. Conclusion: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols.

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