Domain 5 of cleaved high molecular weight kininogen inhibits endothelial cell migration through Akt

Katkade, Vaibhav; Soyombo, Abigail A.; Isordia‐Salas, Irma; Bradford, Harlan N.; Gaughan, John; Colman, Robert W.; Panetti, Tracee Scalise

doi:10.1160/th04-12-0834

Cited by 14 publications

(11 citation statements)

References 41 publications

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“…The concentration (600 nmol/L) used is lower than the dose necessary for the inhibition of EC migration. 17 As indicated in Figure 3D, ␣v␤3 integrin formed a complex with uPAR and caveolin-1 only in the membrane rafts, but not in the nonraft fractions. D5 dissociated uPAR and caveolin-1 from ␣v␤3 integrin in the membrane rafts ( Figure 3D), suggesting D5 disrupts this complex formation via binding to membrane rafts.…”

Section: D5 Dissociates Upar-␣v␤3 Integrin Complex In the Membrane Ramentioning

confidence: 75%

“…Because the association of uPAR with ␣v␤3 integrin is resistant to removal of cholesterol, the interaction between uPAR and ␣v␤3 integrin seems direct, in agreement with the finding of Degryse et al that direct binding of uPAR to ␣v␤3 integrin occurs a region of uPAR domain 2. 29 Because D5 binds to the D2 domain of uPAR, and an antibody against uPAR restores HKa inhibition of EC migration on Vn, 17 uPAR is a primary binding site for HKa inhibition of ␣v␤3 integrin function. D5 occupancy of uPAR may not only block internalization of both receptors and the turnover of focal adhesion plaques during EC migration, but also prevent the assembly of reexpressed uPAR and integrin on the membrane surface during receptor cycling.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Kininostatin Associates With Membrane Rafts and Inhibits αvβ3 Integrin Activation in Human Umbilical Vein Endothelial Cells

Rizzo

Liu

et al. 2007

ATVB

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Objective-The cleaved form of high molecular weight kininogen (HKa) is a potent inhibitor of angiogenesis and tumor growth in vivo; the functional domain has been identified as domain 5 (D5, named as kininostatin). We now identify the subcellular targeting site for D5 on endothelial cells (ECs), and investigate D5 inhibition of integrin functions. Methods and Results-Endothelial membrane rafts were isolated using sucrose density gradient centrifugation. D5, bound to ECs, was predominantly associated with membrane rafts, in which uPAR, a HKa receptor, was also localized. In contrast, other HKa receptors, cytokeratin-1 and gC1q receptor, were not detected in membrane rafts. Colocalization of D5 with caveolin-1 was demonstrated on ECs by confocal microscopy. Disruption of membrane rafts by cholesterol removal decreased D5 binding to ECs. On stimulation with vascular endothelial growth factor, ␣v␤3 integrin formed a complex with uPAR and caveolin-1, which was accompanied by an increase in ligand binding affinity of ␣v␤3 integrin. These events were inhibited by D5. Consistently, D5 suppressed specific ␣v␤3 integrin-mediated EC adhesion and spreading as well as small guanosine triphosphatase Rac1 activation. Key Words: kininogen Ⅲ membrane rafts Ⅲ integrin Ⅲ uPAR Ⅲ angiogenesis C aveolae are specialized components of membrane rafts, 1 which are plasmalemmal invaginations formed by the sequestration of cholesterol and glycosphingolipids with selfassociating molecules named caveolins. The major structural protein of endothelial caveolae is caveolin-1. Because the definitive identification of caveolae in experimental protocols can be only made by electron microscopy, we use the term membrane rafts in most of this paper and indicate when they contain caveolin. Caveolae are abundant on the surface of endothelial cells (ECs). 2 Caveolae and caveolin-1 are widely involved in the regulation of EC function, including EC proliferation, migration, and angiogenesis. Angiogenesis is the process of formation of new blood vessels from the existing microvessels, initiated by stimulation of vascular ECs with growth factors and cytokines. The functional significance of caveolae in angiogenesis has been suggested by defective nitric oxide-dependent angiogenesis in caveolin-1-null mice, 3 and by reduced tube formation in the absence of caveolin-1 in vivo and in vitro. 4 Integrins, particularly the ␣v integrin family, are major players in each step of angiogenesis. 5 Interaction of integrins with extracellular matrix (ECM) is required for EC function and maturation of newly formed blood vessels. ␣v integrins, highly expressed on activated ECs during angiogenesis, colocalize with caveolin-1 in membrane rafts. 6 Downstream effectors of integrins such as Src family kinases, and small guanosine triphosphatases are localized in membrane rafts and are involved in regulation of integrin activation as well as integrin-mediated cytoskeletal rearrangement. 7 Human plasma high molecular weight kininogen (HK) is a major component (660 nmol/L) of th...

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Section: D5 Dissociates Upar-␣v␤3 Integrin Complex In the Membrane Ramentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Kininostatin Associates With Membrane Rafts and Inhibits αvβ3 Integrin Activation in Human Umbilical Vein Endothelial Cells

Rizzo

Liu

et al. 2007

ATVB

Self Cite

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“…21,39 However, PI3K and p44/42 MAPK signaling pathway are less important to S1P-induced vascular endothelial cell migration. 21,28,[40][41][42] Furthermore, whether the involvement of the p38 MAPK pathway is important to S1P-induced vascular endothelial cell migration remains unclear. 21,28 In this study, we found that inhibition of PLC activation and chelation of intracellular Ca 2ϩ ions by treatment with U73122 and BAPTA-AM resulted in a significant reduction in S1P-induced migration and tube formation, as well as Ca 2ϩ influx to lymphatic endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways

Yoon

Hong

Moon

et al. 2008

Blood

115

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The lymphatic system plays pivotal roles in mediating tissue fluid homeostasis and immunity, and excessive lymphatic vessel formation is implicated in many pathological conditions, which include inflammation and tumor metastasis. However, the molecular mechanisms that regulate lymphatic vessel formation remain poorly characterized. Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that is implicated in a variety of biologic processes such as inflammatory responses and angiogenesis. Here, we first report that S1P acts as a lymphangiogenic mediator. S1P induced migration, capillarylike tube formation, and intracellular Ca 2؉ mobilization, but not proliferation, in human lymphatic endothelial cells (HLECs) in vitro. Moreover, a Matrigel plug assay demonstrated that S1P promoted the outgrowth of new lymphatic vessels in vivo. HLECs expressed S1P1 and S1P3, and both RNA interference-mediated down-regulation of S1P1 and an S1P1 antagonist significantly blocked S1P-mediated lymphangiogenesis. Furthermore, pertussis toxin, U73122, and BAPTA-AM efficiently blocked S1P-induced in vitro lymphangiogenesis and intracellular Ca 2؉ mobilization of HLECs, indicating that S1P promotes lymphangiogenesis by stimulating S1P1/G i /phospholipase C/Ca 2؉ signaling pathways. Our results suggest that S1P is the first lymphangiogenic bioactive lipid to be identified, and that S1P and its receptors might serve as new therapeutic targets against inflammatory diseases and lymphatic metastasis in tumors. (Blood. 2008; 112:1129-1138) IntroductionSphingosine-1-phosphate (S1P) has been implicated in a wide spectrum of biologic processes, including the promotion of cell growth and survival, migration and differentiation, platelet aggregation, inflammatory responses, and angiogenesis. 1 S1P is generated by the phosphorylation of sphingosine through a process mediated by sphingosine kinase 1 (SphK1) and SphK2. S1P acts both intracellularly as a second messenger 2 and extracellularly as a ligand for a family of G-protein-coupled S1P receptors. 3 S1P1 couples stringently to the G i protein family, whereas S1P2 and S1P3 couple to the G i , G q , and G 12/13 protein families. Multiple interconnections of S1P signaling through S1P1 and S1P3 induce vascular endothelial cell proliferation, migration, morphogenesis, cytoskeletal reorganization, and adherens junction assembly, whereas signaling via S1P2 negatively regulates S1P-mediated multiple responses of vascular endothelial cells. 4 The defective vascular maturation observed in S1P1-deficient mice highlights a fundamental role for S1P signaling on vasculogenesis. 5 Neutralization of the action of extracellular S1P shows significant inhibition of angiogenesis, tumor growth, metastasis, and lymphocyte transmigration, indicating that S1P is an important pathological regulator of inflammation and angiogenesis. [6][7][8] Lymphatic vessels play important roles in mediating tissue fluid homeostasis and immunity. 9 Although lymphangiogenesis, the formation of new lymphatic vessels from preexisting ves...

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“…HKa and recombinant D5 (also named kininostatin, Ref. 103) inhibit proliferation, migration, and survival of cultured endothelial cells (103, 226,277,640). Inhibition of endothelial cell proliferation is Zn 2ϩ dependent and interferes with the mitogenic effects of bFGF, VEGF, HGF, and PDGF (640) by blocking the transition from G 1 to S phase of the cell cycle (226).…”

Section: Cleaved High-molecular-weight Kininogenmentioning

confidence: 99%

Peptide Hormone Regulation of Angiogenesis

Clapp

Thebault²,

Jeziorski³

et al. 2009

Physiological Reviews

166

158

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It is now apparent that regulation of blood vessel growth contributes to the classical actions of hormones on development, growth, and reproduction. Endothelial cells are ideally positioned to respond to hormones, which act in concert with locally produced chemical mediators to regulate their growth, motility, function, and survival. Hormones affect angiogenesis either directly through actions on endothelial cells or indirectly by regulating proangiogenic factors like vascular endothelial growth factor. Importantly, the local microenvironment of endothelial cells can determine the outcome of hormone action on angiogenesis. Members of the growth hormone/prolactin/placental lactogen, the renin-angiotensin, and the kallikrein-kinin systems that exert stimulatory effects on angiogenesis can acquire antiangiogenic properties after undergoing proteolytic cleavage. In view of the opposing effects of hormonal fragments and precursor molecules, the regulation of the proteases responsible for specific protein cleavage represents an efficient mechanism for balancing angiogenesis. This review presents an overview of the actions on angiogenesis of the above-mentioned peptide hormonal families and addresses how specific proteolysis alters the final outcome of these actions in the context of health and disease.

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Domain 5 of cleaved high molecular weight kininogen inhibits endothelial cell migration through Akt

Cited by 14 publications

References 41 publications

Kininostatin Associates With Membrane Rafts and Inhibits αvβ3 Integrin Activation in Human Umbilical Vein Endothelial Cells

Kininostatin Associates With Membrane Rafts and Inhibits αvβ3 Integrin Activation in Human Umbilical Vein Endothelial Cells

Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways

Peptide Hormone Regulation of Angiogenesis

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