scholarly journals Lactate Engages Receptor Tyrosine Kinases Axl, Tie2, and Vascular Endothelial Growth Factor Receptor 2 to Activate Phosphoinositide 3-Kinase/Akt and Promote Angiogenesis

2013 ◽  
Vol 288 (29) ◽  
pp. 21161-21172 ◽  
Author(s):  
Guo-Xiang Ruan ◽  
Andrius Kazlauskas
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Akt Pathway ◽  
Vegf Receptor ◽  
Vascular Perfusion ◽  
Phosphoinositide 3 Kinase ◽  
High Level ◽  
Aortic Explants

Although a high level of lactate is quintessential to both tumors and wound healing, the manner by which lactate impacts endothelial cells to promote angiogenesis and thereby create or restore vascular perfusion to growing tissues has not been fully elucidated. Here we report that lactate activated the PI3K/Akt pathway in primary human endothelial cells. Furthermore, activating this signaling pathway was required for lactate-stimulated organization of endothelial cells into tubes and for sprouting of vessels from mouse aortic explants. Lactate engaged the PI3K/Akt pathway via ligand-mediated activation of the three receptor tyrosine kinases Axl, Tie2, and VEGF receptor 2. Neutralizing the ligands for these receptor tyrosine kinases, pharmacologically inhibiting their kinase activity or suppressing their expression largely eliminated the ability of cells and explants to respond to lactate. Elucidating the mechanism by which lactate communicates with endothelial cells presents a previously unappreciated opportunity to improve our understanding of the angiogenic program and to govern it.

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.

VEGF-A-stimulated signalling in endothelial cells via a dual receptor tyrosine kinase system is dependent on co-ordinated trafficking and proteolysis

2009 ◽  
Vol 37 (6) ◽  
pp. 1193-1197 ◽  
Author(s):  
Alexander F. Bruns ◽  
Leyuan Bao ◽  
John H. Walker ◽  
Sreenivasan Ponnambalam
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Endothelial Cell Migration ◽  
Rab Gtpases ◽  
Intracellular Location ◽  
Endosomal Sorting ◽  
Golgi Network

The mammalian endothelium expresses two related but distinct receptor tyrosine kinases, VEGFR1 and VEGFR2 [VEGF (vascular endothelial growth factor) receptor 1 and 2], that regulate the vascular response to a key cytokine, VEGF-A. In the present review, we suggest a model for integrating the signals from these receptor tyrosine kinases by co-ordinating the spatial and temporal segregation of these membrane proteins linked to distinct signalling outputs associated with each intracellular location. Activation of pro-angiogenic VEGFR2 stimulates a programme of tyrosine phosphorylation, ubiquitination and proteolysis. This is linked to ESCRT (endosomal sorting complex required for transport)-mediated recognition of activated VEGFR2 and sorting in endosomes before arrival in lysosomes for terminal degradation. In addition, Rab GTPases regulate key events in VEGFR2 trafficking between the plasma membrane, early and late endosomes, with distinct roles for Rab4a, Rab5a and Rab7a. Manipulation of GTPase levels affects not only VEGFR2 activation and intracellular signalling, but also functional outputs such as VEGF-A-stimulated endothelial cell migration. In contrast, VEGFR1 displays stable Golgi localization that can be perturbed by cell stimuli that elevate cytosolic Ca2+ ion levels. One model is that VEGFR1 translocates from the trans-Golgi network to the plasma membrane via a calcium-sensitive trafficking step. This allows rapid and preferential sequestration of VEGF-A by the higher-affinity VEGFR1, thus blocking further VEGFR2 activation. Recycling or degradation of VEGFR1 allows resensitization of the VEGFR2-dependent signalling pathway. Thus a dual VEGFR system with a built-in negative-feedback loop is utilized by endothelial cells to sense a key cytokine in vascular tissues.

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 Phosphoinositide 3-Kinases p110α and p110β Regulate Cell Cycle Entry, Exhibiting Distinct Activation Kinetics in G1 Phase

2008 ◽  
Vol 28 (8) ◽  
pp. 2803-2814 ◽  
Author(s):  
Miriam Marqués ◽  
Amit Kumar ◽  
Isabel Cortés ◽  
Ana Gonzalez-García ◽  
Carmen Hernández ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tyrosine Kinases ◽  
Control Cell ◽  
Growth Factor Receptor ◽  
Maximum Activity ◽  
S Phase ◽  
Selective Action ◽  
Cell Cycle Entry ◽  
Phosphoinositide 3 Kinase ◽  
Phase Entry

ABSTRACT Phosphoinositide 3-kinase (PI3K) is an early signaling molecule that regulates cell growth and cell cycle entry. PI3K is activated immediately after growth factor receptor stimulation (at the G0/G1 transition) and again in late G1. The two ubiquitous PI3K isoforms (p110α and p110β) are essential during embryonic development and are thought to control cell division. Nonetheless, it is presently unknown at which point each is activated during the cell cycle and whether or not they both control S-phase entry. We found that p110α was activated first in G0/G1, followed by a minor p110β activity peak. In late G1, p110α activation preceded that of p110β, which showed the maximum activity at this time. p110β activation required Ras activity, whereas p110α was first activated by tyrosine kinases and then further induced by active Ras. Interference with p110α and -β activity diminished the activation of downstream effectors with different kinetics, with a selective action of p110α in blocking early G1 events. We show that inhibition of either p110α or p110β reduced cell cycle entry. These results reveal that PI3Kα and -β present distinct activation requirements and kinetics in G1 phase, with a selective action of PI3Kα at the G0/G1 phase transition. Nevertheless, PI3Kα and -β both regulate S-phase entry.

scholarly journals Exploring the Gamut of Receptor Tyrosine Kinases for Their Promise in the Management of Non-Alcoholic Fatty Liver Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1776
Author(s):  
Sayali Bhave ◽  
Han Kiat Ho
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Fatty Liver Disease ◽  
Drug Targets ◽  
Fibroblast Growth Factor Receptor ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Recently, non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant health concern affecting approximately a quarter of the world’s population. NAFLD is a spectrum of liver ailments arising from nascent lipid accumulation and leading to inflammation, fibrosis or even carcinogenesis. Despite its prevalence and severity, no targeted pharmacological intervention is approved to date. Thus, it is imperative to identify suitable drug targets critical to the development and progression of NAFLD. In this quest, a ray of hope is nestled within a group of proteins, receptor tyrosine kinases (RTKs), as targets to contain or even reverse NAFLD. RTKs control numerous vital biological processes and their selective expression and activity in specific diseases have rendered them useful as drug targets. In this review, we discuss the recent advancements in characterizing the role of RTKs in NAFLD progression and qualify their suitability as pharmacological targets. Available data suggests inhibition of Epidermal Growth Factor Receptor, AXL, Fibroblast Growth Factor Receptor 4 and Vascular Endothelial Growth Factor Receptor, and activation of cellular mesenchymal-epithelial transition factor and Fibroblast Growth Factor Receptor 1 could pave the way for novel NAFLD therapeutics. Thus, it is important to characterize these RTKs for target validation and proof-of-concept through clinical trials.

Calcium influx induced by activation of receptor tyrosine kinases in SV40-transfected human corneal endothelial cells

2003 ◽  
Vol 77 (4) ◽  
pp. 485-495 ◽  
Author(s):  
Stefan Mergler ◽  
Haike Dannowski ◽  
Jürgen Bednarz ◽  
Katrin Engelmann ◽  
Christian Hartmann ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Calcium Influx ◽  
Corneal Endothelial Cells ◽  
Human Corneal Endothelial Cells

scholarly journals Regulation of vasculogenesis and angiogenesis by EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1326-1333 ◽  
Author(s):  
Yuichi Oike ◽  
Yasuhiro Ito ◽  
Koichi Hamada ◽  
Xiu-Qin Zhang ◽  
Keishi Miyata ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Receptor Tyrosine Kinases ◽  
Vascular Endothelial Cells ◽  
Mesenchymal Cells ◽  
Ephb Receptor ◽  
Vasculogenesis And Angiogenesis

Although the cellular and molecular mechanisms governing angiogenesis are only beginning to be understood, signaling through endothelial-restricted receptors, particularly receptor tyrosine kinases, has been shown to play a pivotal role in these events. Recent reports show that EphB receptor tyrosine kinases and their transmembrane-type ephrin-B2 ligands play essential roles in the embryonic vasculature. These studies suggest that cell-to-cell repellent effects due to bidirectional EphB/ephrin-B2 signaling may be crucial for vascular development, similar to the mechanism described for neuronal development. To test this hypothesis, we disrupted the precise expression pattern of EphB/ephrin-B2 in vivo by generating transgenic (CAGp-ephrin-B2 Tg) mice that express ephrin-B2 under the control of a ubiquitous and constitutive promoter, CMV enhancer-β-actin promoter-β-globin splicing acceptor (CAG). These mice displayed an abnormal segmental arrangement of intersomitic vessels, while such anomalies were not observed in Tie-2p-ephrin-B2 Tg mice in which ephrin-B2 was overexpressed in only vascular endothelial cells (ECs). This finding suggests that non-ECs expressing ephrin-B2 alter the migration of ECs expressing EphB receptors into the intersomitic region where ephrin-B2 expression is normally absent. CAGp-ephrin-B2 Tg mice show sudden death at neonatal stages from aortic dissecting aneurysms due to defective recruitment of vascular smooth muscle cells to the ascending aorta. EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells plays an essential role in vasculogenesis, angiogenesis, and vessel maturation.

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.

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