A comparision of the abilities of plasma kallikrein, β-factor XIIa, factor XIa and urokinase to activate plasminogen

Miles, Lindsey A.; Greengard, Judith S.; Griffin, John H.

doi:10.1016/0049-3848(83)90244-x

Cited by 98 publications

(63 citation statements)

References 29 publications

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“…The derivative, bFXIIa, lacks the surface binding domain and is less efficient at stimulating plasminogen activation. 16 The low level of plasmin generation observed with bFXIIa was not augmented by polyP 70 , reflecting the requirement of the anion binding domain of aFXIIa for interaction with polyP 70 (Figure 1E; P 5 .71). Inclusion of Zn 21 in the reaction buffer did not further enhance the cofactor function of polyP 70 in this reaction (not shown).…”

Section: Results Afxiia Plasminogen Activator Activity Is Enhanced Bymentioning

confidence: 93%

“…Although the plasminogen activator function of aFXIIa has been described previously, 15,16,31 it has been largely ignored due to unfavorable kinetics. Despite displaying a 20-fold lower catalytic efficacy for plasminogen than for uPA, the relative abundance of FXII (375 nM) in plasma implies that it may be relevant as a plasminogen activator.…”

Section: Discussionmentioning

confidence: 99%

“…The kinetics of the reaction are considered unfavorable 13,15 but FXII is present in plasma at 4 orders of magnitude higher concentrations compared with tPA and uPA. 16,17 During evolution, redundancy has developed in the fibrinolytic system, underscored by the relatively mild abnormalities associated with deficiency in tPA or uPA, whereas the double knockout exhibits a more acute phenotype. 18 Under certain circumstances or within specific milieus, it is plausible that FXIIa contributes to plasmin generation to complement or compensate for tPA and uPA activity and may be potentially relevant in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Mitchell

Lionikiene

Georgiev

et al. 2016

Blood

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Key Points• PolyP significantly augments the plasminogen activator capacity of FXIIa.• Platelet-bound fibrin acts as a reservoir for plasminogen, FXII(a), and polyP.Activated factor XII (FXIIa) has plasminogen activator capacity but its relative contribution to fibrinolysis is considered marginal compared with urokinase and tissue plasminogen activator. Polyphosphate (polyP) is released from activated platelets and mediates FXII activation. Here, we investigate the contribution of polyP to the plasminogen activator function of aFXIIa. We show that both polyP 70 , of the chain length found in platelets (60-100 mer), and platelet-derived polyP significantly augment the plasminogen activation capacity of aFXIIa. PolyP 70 stimulated the autoactivation of FXII and subsequent plasminogen activation, indicating that once activated, aFXIIa remains bound to polyP 70 . Indeed, complex formation between polyP 70 and aFXIIa provides protection against autodegradation. Plasminogen activation by bFXIIa was minimal and not enhanced by polyP 70 , highlighting the importance of the anion binding site. PolyP 70 did not modulate plasmin activity but stimulated activation of Glu and Lys forms of plasminogen by aFXIIa. Accordingly, polyP 70 was found to bind to FXII, aFXIIa, and plasminogen, but not bFXIIa. Fibrin and polyP 70 acted synergistically to enhance aFXIIa-mediated plasminogen activation. The plasminogen activator activity of the aFXIIa-polyP 70 complex was modulated by C1 inhibitor and histidine-rich glycoprotein, but not plasminogen activator inhibitors 1 and 2. Platelet polyP and FXII were found to colocalize on the activated platelet membrane in a fibrin-dependent manner and decorated fibrin strands extending from platelet aggregates. We show that in the presence of platelet polyP and the downstream substrate fibrin, aFXIIa is a highly efficient and favorable plasminogen activator. Our data are the first to document a profibrinolytic function of platelet polyP. (Blood. 2016;128(24):2834-2845

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Section: Results Afxiia Plasminogen Activator Activity Is Enhanced Bymentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Mitchell

Lionikiene

Georgiev

et al. 2016

Blood

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“…In addition to tPA and uPA, enzymes of the contact pathway have also been shown to activate plasminogen. 157 As plasmin is generated, it cleaves fibrin to generate C-terminal lysine residues that enhance the interaction between tPA, plasminogen, and fibrin, thus contributing to a further enhancement of plasmin generation on the fibrin clot. The fibrinolytic inhibitor thrombin activatable fibrinolysis inhibitor (or carboxypeptidase B2) removes these lysine residues, which attenuates plasminogen activation.…”

Section: Plasmin(ogen) System/fibrinolysismentioning

confidence: 99%

Cross Talk Pathways Between Coagulation and Inflammation

Foley

Conway

2016

Circulation Research

436

414

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Anatomic pathology studies performed over 150 years ago revealed that excessive activation of coagulation occurs in the setting of inflammation. However, it has taken over a century since these seminal observations were made to delineate the molecular mechanisms by which these systems interact and the extent to which they participate in the pathogenesis of multiple diseases. There is, in fact, extensive cross talk between coagulation and inflammation, whereby activation of one system may amplify activation of the other, a situation that, if unopposed, may result in tissue damage or even multiorgan failure. Characterizing the common triggers and pathways are key for the strategic design of effective therapeutic interventions. In this review, we highlight some of the key molecular interactions, some of which are already showing promise as therapeutic targets for inflammatory and thrombotic disorders. (Circ Res.

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“…This is mediated through intracellular signaling initiated by its binding to receptors including uPA receptor (uPAR; CD87), low-density lipoprotein receptorrelated protein receptor (LRP/α2MR), and specific integrins [105][106][107][108][109][110] . In addition, uPA converts plasminogen into serine protease plasmin [111,112] , which in turn breaks down matrix proteins and activates a number of MMPs [113][114][115][116] . uPAR-bound uPA has been shown in a number of studies to be localized to the leading edge of migrating cells [117][118][119] to help ensure a focused degradation of the ECM and liberate matrix-bound proangiogenic factors, including VEGF [120][121][122] and FGF2 [123,124] .…”

Section: Hox Transcription Factors and Angiogenesismentioning

confidence: 99%

HOX transcription factors and the prostate tumor microenvironment

Morgan¹,

Pandha²

2017

JCMT

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It is now well established that the tumor microenvironment plays an essential role in the survival, growth, invasion, and spread of cancer through the regulation of angiogenesis and localized immune responses. This review examines the role of the HOX genes, which encode a family of homeodomain-containing transcription factors, in the interaction between prostate tumors and their microenvironment. Previous studies have established that HOX genes have an important function in prostate cancer cell survival in vitro and in vivo, but there is also evidence that HOX proteins regulate the expression of genes in the cancer cell that influence the tumor microenvironment, and that cells in the microenvironment likewise express HOX genes that confer a tumor-supportive function. Here we provide an overview of these studies that, taken together, indicate that the HOX genes help mediate cross talk between prostate tumors and their microenvironment. Key words:Prostate cancer, tumor microenvironment, HOX, PBX, metastasis, angiogenesis ABSTRACTArticle history:

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A comparision of the abilities of plasma kallikrein, β-factor XIIa, factor XIa and urokinase to activate plasminogen

Cited by 98 publications

References 29 publications

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Cross Talk Pathways Between Coagulation and Inflammation

HOX transcription factors and the prostate tumor microenvironment

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