Identification and Characterization of Prolylcarboxypeptidase as an Endothelial Cell Prekallikrein Activator

Shariat‐Madar, Zia; Mahdi, Fakhri; Schmaier, Alvin H.

doi:10.1074/jbc.m106101200

Cited by 249 publications

(265 citation statements)

References 35 publications

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“…Western blot of equal total protein concentration of the kidney lysates from control and BKB2R Ϫ/Ϫ mice was performed. 1 The primary antibody was a rabbit antihuman antibody to AT 2 R (H143; Santa Cruz Biotechnology, Santa Cruz, CA) at a 1:200 dilution, followed by a goat antirabbit antibody conjugated with horseradish peroxidase (Sigma). The specific reactivity of the antibody with the electroblotted sample was detected with the ECL system from Amersham Biosciences (Piscataway, NJ).…”

Section: Determination Of At 2 R Antigen In Mouse Kidneymentioning

confidence: 99%

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Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin

Shariat‐Madar

Mahdi

Warnock

et al. 2006

Blood

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Section: Determination Of At 2 R Antigen In Mouse Kidneymentioning

confidence: 99%

“…[1][2][3][4][5] Prior to these studies, PRCP had only been known as a BK and angiotensin II (AngII) degrading enzyme. 6,7 Formation of plasma kallikrein and BK is a physiologic pathway because mice deficient in C1 inhibitor, the major plasma kallikrein inhibitor, have constitutive BK-mediated angioedema.…”

Section: Introductionmentioning

confidence: 99%

Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin

Shariat‐Madar

Mahdi

Warnock

et al. 2006

Blood

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103

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“…The plasma concentration of PK and the ambient free Zn 2ϩ concentration in plasma also prevent FXI from binding to HK under conditions where platelets or other cells are not activated (8). PK bound to HK on endothelial cells is proteolyzed by membrane-expressed prolylcarboxypeptidase to form plasma kallikrein (9,10). This multiprotein receptor complex thereby regulates the assembly and activation of the plasma kallikrein/ kinin system.…”

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confidence: 99%

Mapping the Interaction between High Molecular Mass Kininogen and the Urokinase Plasminogen Activator Receptor

Mahdi

Shariat‐Madar

Kuo

et al. 2004

Journal of Biological Chemistry

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The urokinase plasminogen activator receptor (uPAR) is a multifunctional, GPI-linked receptor that modulates cell adhesion/migration and fibrinolysis. We mapped the interaction sites between soluble uPAR (su-PAR) and high molecular mass kininogen (HK). Binding of biotin-HK to suPAR was inhibited by HK, 56HKa, and 46HKa with an IC 50 of 60, 110, and 8 nM, respectively. We identified two suPAR-binding sites, a higher affinity site in the light chain of HK and 46HKa (His 477 -Gly 496 ) and a lower affinity site within the heavy chain (Cys 333 -Lys 345 ). HK predominantly bound to suPAR fragments containing domains 2 and 3 (S-D2D3). Binding of HK to domain 1 (S-D1) was also detected, and the addition of S-D1 to S-D2D3 completely inhibited biotin-HK or -46HKa binding to suPAR. Recent investigations indicate that high molecular mass kininogen (HK)1 binds to endothelial cell membranes through an interaction with a multiprotein receptor complex comprising at least cytokeratin 1, gC1qR, and the urokinase plasminogen activator receptor (uPAR) (1-5). The three proteins co-localize on the endothelial cell membrane (6). The same three proteins form a receptor complex for factor XII (7), but binding of factor XII in vivo is likely limited both by the low plasma concentration of free Zn 2ϩ , which is below the requirement for FXII binding and by the much higher plasma concentration of HK (7). Binding of HK to this multiprotein receptor complex predominates, localizing prekallikrein (PK) to the cell surface. The plasma concentration of PK and the ambient free Zn 2ϩ concentration in plasma also prevent FXI from binding to HK under conditions where platelets or other cells are not activated (8). PK bound to HK on endothelial cells is proteolyzed by membrane-expressed prolylcarboxypeptidase to form plasma kallikrein (9, 10). This multiprotein receptor complex thereby regulates the assembly and activation of the plasma kallikrein/ kinin system.The requirements for HK binding to each component of this receptor complex and the effects of other biologically relevant ligands, e.g. urokinase, on this binding have not been well delineated. It is known that both the heavy and light chains of HK interact with a region of cytokeratin 1 coded by exon 1 (2). Antibody to this region completely inhibits HK binding to cytokeratin 1 as well as to the receptor complex (6). Likewise, some antibodies to gC1qR and uPAR completely block HK binding to the proteins individually as well as when they are part of the complex expressed on endothelial cells (6, 8). However, it is unclear whether each component of the cellular complex recognizes discrete or overlapping portions of HK and whether each molecule of HK binds to more than one component of the complex at the same time. To begin to address these issues, we sought to identify the regions in HK and uPAR required for binding. The results indicate the existence of multiple potential sites of interaction between this ligand and receptor and provide insight into the assembly of HK on its multireceptor co...

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“…The binding of HK to endothelial cells via cytokeratin 1 (CK1) (38) and complement C1q receptor (gC1qR) (39,40) is well established and plays an important role in activation of the plasma KKS on cell surface (41)(42)(43). Although previous studies indicated that HK did not bind to urokinase plasminogen activator receptor (uPAR) (41), emerging evidence suggests that the unique regions of HK might serve as urokinase-binding sites (45).…”

Section: Discussionmentioning

confidence: 99%

High Molecular Weight Kininogen Activates B2 Receptor Signaling Pathway in Human Vascular Endothelial Cells

Kolte

Osman

Yang

et al. 2011

Journal of Biological Chemistry

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The nonenzymatic cofactor high molecular weight kininogen (HK) is a precursor of bradykinin (BK). The production of BK from HK by plasma kallikrein has been implicated in the pathogenesis of inflammation and vascular injury. However, the functional role of HK in the absence of prekallikrein (PK), the proenzyme of plasma kallikrein, on vascular endothelial cells is not fully defined. In addition, no clinical abnormality is seen in PKdeficient patients. Therefore, an investigation into the effect of HK, in the absence of PK, on human pulmonary artery endothe- The plasma kallikrein-kinin system (KKS) 2 consists of three proenzymes; factor XII (FXII, Hageman factor), prekallikrein (PK, Fletcher factor), and factor XI (FXI, plasma thromboplastin antecedent) as well as one cofactor; high molecular weight kininogen (HK, Fitzgerald factor). KKS is involved in the regulation of hemodynamics, inflammation, complement activation, angiogenesis, thrombosis, and fibrinolysis. Basically, all these proposed roles represent a range of overlapping effects that contribute to various extents toward vasodilation and healing. Therefore, the plasma KKS can be considered to have a spectrum of physiological effects, ranging at one extreme from a hemostatic state of vasodilation and promotion of smooth blood flow, all the way to a prothrombotic state. It is conceivable to suggest that other mechanisms proposed about respiratory, retinal, and renal systems can fit into this spectrum of physiological effects (1-3). There is accumulating evidence suggesting that when the plasma KKS is activated, the results are a sequential release of proteolytic enzymes and vasoactive peptides, generation of both angiogenic and anti-angiogenic molecules, stabilization of thrombus, and an increase in protease inhibitor activity in blood (4 -7). The activation of HK-PK complex on endothelial cells triggers vasodilation through smooth muscle relaxation, inhibits platelet aggregation, and induces proinflammatory responses. Of note, the direct assembly of HK, PK, and FXII on vascular smooth muscle cells (VSMC) also results in the activation of PK to kallikrein (8). The induction of these physiological reactions is caused by the release of the vasoactive peptide bradykinin (BK) from HK by kallikrein. Bradykinin B 2 receptor activation by BK mediates the activation of endothelial nitric-oxide synthase (eNOS) and phospholipase A 2 (PLA 2 ) leading to production of nitric oxide (NO) and prostacylin (PGI 2 ). Evidence suggests that BK phosphorylates p44/42 mitogen-activated protein kinase in VMSC, which is blocked by BK antagonist HOE-140 (8).Besides having a direct effect on blood vessels, the HK-PK complex has also been shown to mediate the effects of other pro-inflammatory molecules. Recent study suggests that the inhibitors of both BK and factor XII activity protect from mast cell-induced effects not only in patients but also in genetically engineered mouse models. The authors proposed that this class of inhibitors could be useful to treat allergic diseases (9)....

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Identification and Characterization of Prolylcarboxypeptidase as an Endothelial Cell Prekallikrein Activator

Cited by 249 publications

References 35 publications

Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin

Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin

Mapping the Interaction between High Molecular Mass Kininogen and the Urokinase Plasminogen Activator Receptor

High Molecular Weight Kininogen Activates B2 Receptor Signaling Pathway in Human Vascular Endothelial Cells

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