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.

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.

scholarly journals Perforation of the Small Intestine after Introduction of Lenvatinib in a Patient with Advanced Hepatocellular Carcinoma

2020 ◽  
Vol 14 (1) ◽  
pp. 63-69 ◽  
Author(s):  
Naomi Suzuki ◽  
Kazuto Tajiri ◽  
Yuka Futsukaichi ◽  
Shinichi Tanaka ◽  
Aiko Murayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Small Intestine ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Vegf Receptor ◽  
Advanced Hepatocellular Carcinoma ◽  
Vascular Endothelial ◽  
First Line ◽  
Endothelial Growth Factor ◽  
Line Standard

Lenvatinib is a first-line standard treatment for advanced hepatocellular carcinoma (HCC) with better anti-tumor effects than sorafenib, as shown by greater inhibition of the kinases of fibroblast growth factor receptor and vascular endothelial growth factor (VEGF) receptor. This report describes a patient with advanced HCC who experienced perforation of the small intestine 1 month after starting the treatment with lenvatinib. This patient likely had partial necrosis of a metastasis to the small intestine before starting lenvatinib treatment, with subsequent ischemic changes leading to perforation of the small intestine. Although metastasis of HCC to the small intestine is rare, patients with these metastases should be regarded as being at risk for perforation during lenvatinib treatment.

scholarly journals The VEGF inhibitor vatalanib regulates AD pathology in 5xFAD mice

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Seong Gak Jeon ◽  
Hyun-ju Lee ◽  
HyunHee Park ◽  
Kyung-Min Han ◽  
Hyang-Sook Hoe
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Tau Phosphorylation ◽  
Vascular Endothelial ◽  
Epidemiological Evidence ◽  
Beneficial Effects ◽  
Vegf Inhibitor ◽  
Gsk 3Β ◽  
5Xfad Mice ◽  
Endothelial Growth Factor

Abstract Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disease characterized by Aβ accumulation and tau hyperphosphorylation. Epidemiological evidence for a negative correlation between cancer and AD has led to the proposed use of tyrosine kinase inhibitors (TKIs) such as dasatinib and masitinib for AD, with reported beneficial effects in the AD brain. The TKI vatalanib inhibits angiogenesis by inhibiting vascular endothelial growth factor receptor (VEGFR). Although changes in VEGF and VEGFR have been documented in AD, the effect of vatalanib on AD pathology has not been investigated. In this study, the effects of vatalanib on tau phosphorylation and Aβ accumulation in 5xFAD mice, a model of AD, were evaluated by immunohistochemistry. Vatalanib administration significantly reduced tau phosphorylation at AT8 and AT100 by increasing p-GSK-3β (Ser9) in 5xFAD mice. In addition, vatalanib reduced the number and area of Aβ plaques in the cortex in 5xFAD mice. Our results suggest that vatalanib has potential as a regulator of AD pathology.

Neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors

Neurology ◽  
2019 ◽  
Vol 93 (2) ◽  
pp. e143-e148 ◽  
Author(s):  
Bhaskar Roy ◽  
Avash Das ◽  
Kumar Ashish ◽  
Dhrubajyoti Bandyopadhyay ◽  
Abhishek Maiti ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Sensory Neuropathy ◽  
Vascular Endothelial ◽  
High Grade ◽  
Patients With Cancer ◽  
Endothelial Growth Factor ◽  
Receptor Tyrosine Kinase Inhibitors

ObjectiveTo explore the association of peripheral neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) use in patients with cancer.MethodsPublished data search up to November 2018 reporting peripheral neuropathy in patients with cancer treated with VEGFR-TKIs was performed. The primary outcome was presence of peripheral neuropathy at the end of the trial. Random-effects meta-analysis was performed to estimate relative risk (RR) of individual treatment.ResultsThirty randomized clinical trials (RCTs) including 12,490 patients with cancer were included in this analysis. Eight studies compared VEGFR-TKIs with placebo and the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. When compared against placebo, VEGFR-TKIs were associated with a higher risk of peripheral neuropathy (RR 1.76; 95% confidence interval [CI] 1.13–2.75, p = 0.01). Similarly, a stronger association was noted for sensory neuropathy with VEGFR-TKIs monotherapy (RR 1.61; 95% CI 1.09–2.37, p = 0.02). Risk of peripheral neuropathy with VEGFR-TKIs was higher even when they were compared against control (either placebo or standard chemotherapeutic agents) (RR 1.08; 95% CI 1.01–1.15, p = 0.03). High-grade neuropathy (RR 1.28; 95% CI 1.06–1.54, p <0.01) and high-grade sensory neuropathy (RR 1.38; 95% CI 1.09–1.74, p < 0.01) were noted more frequently with VEGFR-TKIs treatment compared against control.ConclusionsVEGFR-TKIs therapy appeared to be associated with an increased risk of neuropathy.

scholarly journals Quantifying the strength of heterointeractions among receptor tyrosine kinases from different subfamilies: Implications for cell signaling

2020 ◽  
Vol 295 (29) ◽  
pp. 9917-9933 ◽  
Author(s):  
Michael D. Paul ◽  
Hana N. Grubb ◽  
Kalina Hristova
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Eph Receptor ◽  
Vital Cell ◽  
Cell Processes ◽  
Epidermal Growth ◽  
Endothelial Growth Factor

Receptor tyrosine kinases (RTKs) are single-pass membrane proteins that control vital cell processes such as cell growth, survival, and differentiation. There is a growing body of evidence that RTKs from different subfamilies can interact and that these diverse interactions can have important biological consequences. However, these heterointeractions are often ignored, and their strengths are unknown. In this work, we studied the heterointeractions of nine RTK pairs, epidermal growth factor receptor (EGFR)–EPH receptor A2 (EPHA2), EGFR–vascular endothelial growth factor receptor 2 (VEGFR2), EPHA2–VEGFR2, EPHA2–fibroblast growth factor receptor 1 (FGFR1), EPHA2–FGFR2, EPHA2–FGFR3, VEGFR2–FGFR1, VEGFR2–FGFR2, and VEGFR2–FGFR3, using a FRET-based method. Surprisingly, we found that RTK heterodimerization and homodimerization strengths can be similar, underscoring the significance of RTK heterointeractions in signaling. We discuss how these heterointeractions can contribute to the complexity of RTK signal transduction, and we highlight the utility of quantitative FRET for probing multiple interactions in the plasma membrane.

Sign in / Sign up

Export Citation Format

Share Document