scholarly journals Tyrosine phosphatase PTP-MEG2 negatively regulates vascular endothelial growth factor receptor signaling and function in endothelial cells

2012 ◽  
Vol 303 (5) ◽  
pp. C548-C553 ◽  
Author(s):  
Qin Hao ◽  
Buka Samten ◽  
Hong-Long Ji ◽  
Z. Joe Zhao ◽  
Hua Tang
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Protein Tyrosine ◽  
Vegfr2 Signaling ◽  
And Function ◽  
Endothelial Growth Factor

Protein tyrosine phosphorylation is a fundamental mechanism for diverse physiological processes, which is regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs). In this study, we searched for protein substrates of PTP-MEG2 (also called PTPN9), a nonreceptor PTP, and investigated its function in endothelial cells (ECs). By using a PTP-MEG2 substrate-trapping DA mutant, we found that a couple of tyrosine-phosphorylated proteins were associated with the DA mutant but not wild-type PTP-MEG2 and that the association was enhanced by vascular endothelial growth factor (VEGF) in ECs. We further found that VEGF receptor 2 (VEGFR2) was coimmunopricipitated with the DA mutant but not wild-type PTP-MEG2. The VEGF-induced phosphorylation of VEGFR2 on Tyr1175, a critical autophosphorylation site for VEGFR2 signaling, was inhibited 70% by overexpression of wild-type PTP-MEG2 but was enhanced (2.2-fold) by the DA mutant of PTP-MEG2. We also found that PTP-MEG2 DA mutant preferentially associated with Janus kinase 1 (JAK1) but not with other JAK kinases (Tyk2 and JAK2) present in ECs and regulated JAK1 tyrosine phosphorylation. Lastly, the VEGF-induced signal transduction and the production of interleukin (IL)-6 were significantly enhanced by PTP-MEG2 knockdown in ECs, whereas the VEGF-induced IL-6 production was inhibited 50% by PTP-MEG2 overexpression. Thus we have indentified VEGFR2 as a PTP-MEG2 substrate, and our findings indicate that PTP-MEG2 is a negative regulator of VEGFR2 signaling and function in ECs.

scholarly journals Vascular Endothelial Growth Factor D Is Dispensable for Development of the Lymphatic System

2005 ◽  
Vol 25 (6) ◽  
pp. 2441-2449 ◽  
Author(s):  
Megan E. Baldwin ◽  
Michael M. Halford ◽  
Sally Roufail ◽  
Richard A. Williams ◽  
Margaret L. Hibbs ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Tissue Mass ◽  
And Function ◽  
Endothelial Growth Factor ◽  
Deficient Mice

ABSTRACT Vascular endothelial growth factor receptor 3 (Vegfr-3) is a tyrosine kinase that is expressed on the lymphatic endothelium and that signals for the growth of the lymphatic vessels (lymphangiogenesis). Vegf-d, a secreted glycoprotein, is one of two known activating ligands for Vegfr-3, the other being Vegf-c. Vegf-d stimulates lymphangiogenesis in tissues and tumors; however, its role in embryonic development was previously unknown. Here we report the generation and analysis of mutant mice deficient for Vegf-d. Vegf-d-deficient mice were healthy and fertile, had normal body mass, and displayed no pathologic changes consistent with a defect in lymphatic function. The lungs, sites of strong Vegf-d gene expression during embryogenesis in wild-type mice, were normal in Vegf-d-deficient mice with respect to tissue mass and morphology, except that the abundance of the lymphatics adjacent to bronchioles was slightly reduced. Dye uptake experiments indicated that large lymphatics under the skin were present in normal locations and were functional. Smaller dermal lymphatics were similar in number, location, and function to those in wild-type controls. The lack of a profound lymphatic phenotype in Vegf-d-deficient mice suggests that Vegf-d does not play a major role in lymphatic development or that Vegf-c or another, as-yet-unknown activating Vegfr-3 ligand can compensate for Vegf-d during development.

Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells

1998 ◽  
Vol 111 (13) ◽  
pp. 1853-1865 ◽  
Author(s):  
S. Esser ◽  
M.G. Lampugnani ◽  
M. Corada ◽  
E. Dejana ◽  
W. Risau
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Vascular Permeability ◽  
Tyrosine Phosphorylation ◽  
Adherens Junction ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Cell Cell

Interendothelial junctions play an important role in the regulation of endothelial functions, such as vasculogenesis, angiogenesis, and vascular permeability. In this paper we show that vascular endothelial growth factor (VEGF), a potent inducer of new blood vessels and vascular permeability in vivo, stimulated the migration of endothelial cells after artificial monolayer wounding and induced an increase in paracellular permeability of human umbilical vein endothelial cells (HUVECs). Furthermore, VEGF increased phosphotyrosine labeling at cell-cell contacts. Biochemical analyses revealed a strong induction of VEGF-receptor-2 (flk-1/KDR) tyrosine-autophosphorylation by VEGF which was maximal after 5 minutes and was followed by receptor downregulation. 15 minutes to 1 hour after VEGF stimulation the endothelial adherens junction components VE-cadherin, beta-catenin, plakoglobin, and p120 were maximally phosphorylated on tyrosine, while alpha-catenin was not modified. PECAM-1/CD31, another cell-cell junctional adhesive molecule, was tyrosine phosphorylated with similar kinetics in response to VEGF. In contrast, activation of VEGF-receptor-1 (Flt-1) by its specific ligand placenta growth factor (PlGF) had no effect on the tyrosine phosphorylation of cadherins and catenins. Despite the rapid and transient receptor activation and the subsequent tyrosine phosphorylation of adherens junction proteins the cadherin complex remained stable and associated with junctions. Our results demonstrate that the endothelial adherens junction is a downstream target of VEGFR-2 signaling and suggest that tyrosine phosphorylation of its components may be involved in the the loosening of cell-cell contacts in established vessels to modulate transendothelial permeability and to allow sprouting and cell migration during angiogenesis.

scholarly journals Src-mediated Phosphorylation of Hsp90 in Response to Vascular Endothelial Growth Factor (VEGF) Is Required for VEGF Receptor-2 Signaling to Endothelial NO Synthase

2007 ◽  
Vol 18 (11) ◽  
pp. 4659-4668 ◽  
Author(s):  
Martine Duval ◽  
Fabrice Le Bœuf ◽  
Jacques Huot ◽  
Jean-Philippe Gratton
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
No Synthase ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Endothelial No Synthase ◽  
No Release ◽  
Endothelial Growth Factor

Nitric oxide (NO) release from endothelial cells, via endothelial NO synthase (eNOS) activation, is central to the proangiogenic actions of vascular endothelial growth factor (VEGF). VEGF signaling to eNOS is principally mediated by an Akt-dependent phosphorylation of eNOS and by increased association of eNOS to the molecular chaperone, heat-shock protein 90 kDa (Hsp90). Herein, we report that VEGFR-2 activation induces tyrosine phosphorylation of VEGF receptor 2 (VEGFR-2)-associated Hsp90β. Tyrosine phosphorylation of Hsp90β in response to VEGF is dependent on internalization of the VEGFR-2 and on Src kinase activation. Furthermore, we demonstrate that c-Src directly phosphorylates Hsp90 on tyrosine 300 residue and that this event is essential for VEGF-stimulated eNOS association to Hsp90 and thus NO release from endothelial cells. Our work identifies Y300 phosphorylation of Hsp90 as a novel regulated posttranslational modification of the chaperone and demonstrates its importance in the proangiogenic actions of VEGF, namely by regulating NO release from endothelial cells.

scholarly journals A Role for Cadherin-5 in Regulation of Vascular Endothelial Growth Factor Receptor 2 Activity in Endothelial Cells

1999 ◽  
Vol 10 (10) ◽  
pp. 3401-3407 ◽  
Author(s):  
Nader Rahimi ◽  
Andrius Kazlauskas
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Cell Density ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Cell Contact ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

FLK-1/vascular endothelial growth factor receptor 2 (VEGFR-2) is one of the receptors for VEGF. In this study we examined the effect of cell density on activation of VEGFR-2. VEGF induces only very slight tyrosine phosphorylation of VEGFR-2 in confluent (95–100% confluent) pig aortic endothelial (PAE) cells. In contrast, robust VEGF-dependent tyrosine phosphorylation of VEGFR-2 was observed in cells plated in sparse culture conditions (60–65% confluent). A similar cell density-dependent phenomenon was observed in different endothelial cells but not in NIH-3T3 fibroblast cells expressing VEGFR-2. Stimulating cells with high concentrations of VEGF or replacing the extracellular domain of VEGFR-2 with that of the colony-stimulating factor 1 receptor did not alleviate the sensitivity of VEGFR-2 to cell density, indicating that the confluent cells were probably not secreting an antagonist to VEGF. Furthermore, in PAE cells, ectopically introduced platelet-derived growth factor α receptor could be activated at both high and low cell density conditions, indicating that the density effect was not universal for all receptor tyrosine kinases expressed in endothelial cells. In addition to lowering the density of cells, removing divalent cations from the medium of confluent cells potentiated VEGFR-2 phosphorylation in response to VEGF. These findings suggested that cell–cell contact may be playing a role in regulating the activation of VEGFR-2. To this end, pretreatment of confluent PAE cells with a neutralizing anti-cadherin-5 antibody potentiated the response of VEGFR-2 to VEGF. Our data demonstrate that endothelial cell density plays a critical role in regulating VEGFR-2 activity, and that the underlying mechanism appears to involve cadherin-5.

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