Negative regulation of urokinase-type plasminogen activator production through FGF-2-mediated activation of phosphoinositide 3-kinase

Mochizuki, Yoshinari; Tsuda, Satoshi; Kanetake, Hiroshi; Kanda, Shigeru

doi:10.1038/sj.onc.1205736

Cited by 20 publications

(17 citation statements)

References 43 publications

(33 reference statements)

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“…21 To investigate whether PI3 kinase was activated by ephrin-B2/Fc, HUVECs were stimulated with 1 g/mL of ephrin-B2/Fc and lysed, and PI3 kinase activity in anti-phosphotyrosine immunoprecipitates was examined by thin-layer chromatography. 10 As shown in Figure 2, PI3 kinase activity in immunoprecipitates of antiphosphotyrosine antibodies from HUVECs was increased by ephrin-B2/Fc stimulation, suggesting that ephrin-B2/Fc induced tyrosine phoshorylation of a specific protein in HUVECs, followed by association with PI3 kinase and activation of PI3-kinase.…”

Section: Ephrin-b2/fc Increases Pi3 Kinase Activity In Huvecsmentioning

confidence: 73%

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Ephrin-B2 Induces Migration of Endothelial Cells Through the Phosphatidylinositol-3 Kinase Pathway and Promotes Angiogenesis in Adult Vasculature

Maekawa

Oike

Kanda

et al. 2003

ATVB

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Objective-Ephrin-B2 plays a key role in vascular development. The purpose of this study was to elucidate the molecular mechanisms of ephrin-B2 signaling through the EphB receptor in endothelial cells and to determine whether ephrin-B2 contributes to in vivo angiogenesis in adult mice. Methods and Results-A chemotaxis assay on a polycarbonate membrane revealed that ephrin-B2/Fc chimeric protein induced migration of human umbilical vein endothelial cells (HUVECs) at a level 98% greater than control (PϽ0.01).To determine the signaling pathways activated in the HUVECs by Eph stimulation, phosphatidylinositol-3 kinase (PI3 kinase) activity was determined in an immune complex PI3 kinase assay. Serum-starved HUVECs were stimulated with ephrin-B2/Fc and compared with unstimulated cells. PI3 kinase activity in stimulated cells was higher than that seen in unstimulated cells. In a chemotaxis assay, the PI3 kinase-specific inhibitor LY294002 blocked the migratory response of HUVECs induced by addition of ephrin-B2/Fc. Finally, ephrin-B2/Fc promoted angiogenesis in vivo in corneal neovascularization and Matrigel plug assays in adult mice, whereas LY294002 reduced angiogenesis in Matrigel that was induced by ephrin-B2/Fc. Key Words: ephrin-B2 Ⅲ angiogenesis Ⅲ phosphatidylinositol-3 kinase Ⅲ migration Ⅲ endothelial cells E ph receptor tyrosine kinases (RTKs) constitute the largest known family of RTKs identified, consisting of at least 14 receptors and 8 ephrin ligands. 1,2 Unlike most soluble RTK ligands, ephrins are membrane-attached cell surface molecules. 1 It has been shown that the ephrins and Ephs play essential roles in vascular development during embryogenesis. 3 Targeted mutation of ephrin-B2 in mice results in embryonic lethality at embryonic day 10.5 in homozygous nulls. 3 In these mice, vascular development is arrested at the primary plexus stage, and features of angiogenic remodeling are not observed. 3 Mouse embryos lacking EphB4 essentially phenocopy defects observed in ephrin-B2-null mice, suggesting reciprocal functions for the 2 molecules during vascular development in the embryo. 4 By contrast, little is known about the function of ephrin-B2 in the adult vasculature. Expression studies indicate that the endothelium of a subset of new vessels strongly expresses ephrin-B2 in adult angiogenesis as in tumor angiogenesis and in the female reproductive system, 5 suggesting that ephrin-B2 may play a role in adult angiogenesis. Here, by using in vivo model of angiogenesis in adult mice, we ask whether ephrin-B2 has an angiogenic effect. Conclusions-Ephrin-B2/FcSeveral proteins function in the Eph signaling pathway. Among these, phosphatidylinositol-3 (PI3) kinase, Grb2, Grb10, Nck, RasGAP, and Src are implicated in regulating cell morphology, attachment, and motility. 2,6,7 However, the molecular mechanism of angiogenesis induced by Eph activation has not been elucidated. In this study, we demonstrate that ephrin-B2 induces angiogenesis in vivo and that the PI3 kinase signaling pathway contributes to angiogenic ev...

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Section: Ephrin-b2/fc Increases Pi3 Kinase Activity In Huvecsmentioning

confidence: 73%

“…10 HUVECs were kept in EBM-2 containing 0.5% FBS overnight and either left unstimulated or stimulated with 1 g/mL ephrin-B2/Fc for 5 minutes. HUVECs were lysed and clarified cell lysates were immunoprecipitated with antiphosphotyrosine monoclonal antibody PY-20.…”

Section: Immune Complex Pi3 Kinase Assaymentioning

confidence: 99%

Ephrin-B2 Induces Migration of Endothelial Cells Through the Phosphatidylinositol-3 Kinase Pathway and Promotes Angiogenesis in Adult Vasculature

Maekawa

Oike

Kanda

et al. 2003

ATVB

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“…Few reports show that inhibition of PI3K leads to enhanced gene transcription. For example, PI3K inhibition led to enhanced expression of urokinase like plasminogen activator (Mochizuki et al 2002) and an increase in inducible nitric oxide synthase production (Pahan et al 1999). In our study, one possibility of enhanced WRS expression in the presence of PI3K inhibitors may be that the inhibitors may be activating some other, yet undescribed, pathway for WRS induction, or they could more likely be releasing a PI3K mediated inhibition of another signaling pathway to modulate WRS expression.…”

Section: Discussionmentioning

confidence: 99%

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

Yadav

Burudi

Alirezaei

et al. 2007

Glia

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Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-γ and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-γ in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia. Interestingly, we observed that both IL-4 and IL-13 greatly enhanced IFN-γ induced IDO expression. However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-γ, is downregulated by IL-4 and IL-13. The effect of IL-4 and IL-13 was independent of STAT-6. Modulation of IDO but not WRS was eliminated by inhibition of protein phosphatase 2A (PP2A) activity. The phosphatidylinositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-γ induction of IDO, whereas such inhibition greatly enhanced WRS expression. These findings show discordance between modulations of expression of two distinct enzymes utilizing tryptophan as a common substrate, and raise the possibility of their involvement in regulating immune responses in various neurological disorders.

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“…Rapamycin was dissolved in methanol and kept at À20jC until use. 30), were cultured in Ham's F-12 medium supplemented with 20% heat-inactivated fetal bovine serum (FBS), 75 Ag/mL endothelial cell growth supplement (Sigma), 5 Ag/mL insulin, and 10 ng/mL EGF with or without 200 Ag/mL of G418. HUVECs from three different individuals and their culture medium were obtained from Cambrex, Walkersville, MD, and cells were cultured in endothelial cell basal medium (EBM)-2 supplemented with 2% FBS, 10 ng/mL VEGF-A, 20 ng/mL FGF-2, 10 ng/mL EGF, 10 ng/mL insulin-like growth factor-I, 50 Ag/mL ascorbic acid, 100 ng/mL heparin, and 10 pmol/L dexamethasone.…”

Section: Methodsmentioning

confidence: 99%

Angiopoietin 1 Is Mitogenic for Cultured Endothelial Cells

Kanda¹,

Miyata

Mochizuki

et al. 2005

Cancer Research

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Negative regulation of urokinase-type plasminogen activator production through FGF-2-mediated activation of phosphoinositide 3-kinase

Cited by 20 publications

References 43 publications

Ephrin-B2 Induces Migration of Endothelial Cells Through the Phosphatidylinositol-3 Kinase Pathway and Promotes Angiogenesis in Adult Vasculature

Ephrin-B2 Induces Migration of Endothelial Cells Through the Phosphatidylinositol-3 Kinase Pathway and Promotes Angiogenesis in Adult Vasculature

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

Angiopoietin 1 Is Mitogenic for Cultured Endothelial Cells

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