The cell-binding domains of plasminogen and their function in plasma.

Miles, Lindsey A.; Dahlberg, Carol M.; Plow, Edward F.

doi:10.1016/s0021-9258(18)37875-x

Cited by 129 publications

(26 citation statements)

References 39 publications

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“…One plasminogen fragment with the potential to generate plasmin is a fragment of molecular weight 38 kDa (containing K5) termed ''miniplasminogen'' (Sottrup-Jensen et al, 1978). This fragment is produced from plasminogen by pancreatic elastase and is converted into plasmin by soluble uPA (Sottrup-Jensen et al, 1978); however, the major recognition site for plasminogen binding to cells appears to reside in K1-3 (a fragment that does not contain plasmin activity) and ''miniplasminogen'' has limited ability to bind cells (Miles et al, 1988). These observations support our results that plasminogen incubated with leg ulcer fluid does not generate fragments that are able to bind to keratinocytes and generate plasmin.…”

Section: Discussionmentioning

confidence: 99%

Wound Fluid from Venous Leg Ulcers Degrades Plasminogen and Reduces Plasmin Generation by Keratinocytes

Hoffman

Starkey

Coad

1998

Journal of Investigative Dermatology

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Plasminogen, the pro-enzyme of plasmin, aids various processes essential for normal, acute wound healing, such as fibrinolysis and cell migration. We have investigated if plasminogen is available to perform these functions in chronic wounds such as venous leg ulcers. We report that plasminogen is degraded by fluid from venous leg ulcers to a number of fragments, including kringle domains 1-3, an angiostatin-related protein. The enzyme responsible was inhibited by the serine protease inhibitor phenyl-methylsulfonyl fluoride, but was not inhibited by alpha1-anti-trypsin, an inhibitor of neutrophil elastase, by alpha2-anti-plasmin, an inhibitor of plasmin, or by the matrix metalloprotease inhibitor 1,10 phenanthroline. Plasminogen degraded by wound fluid was a weaker substrate than intact plasminogen for plasmin generation by the keratinocyte cell line HaCaT. These results suggest that serine protease activity in leg ulcer fluid degrades plasminogen and support the hypothesis that keratinocyte migration may be impaired in leg ulcers because of a reduced availability of intact plasminogen for plasmin generation.

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Section: Discussionmentioning

confidence: 99%

Wound Fluid from Venous Leg Ulcers Degrades Plasminogen and Reduces Plasmin Generation by Keratinocytes

Hoffman

Starkey

Coad

1998

Journal of Investigative Dermatology

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“…Multiple receptors for plasminogen have been described in various cell types, but not all cell types express the same receptors 15 . One feature many of these receptors have in common is that they bind plasminogen via its lysine binding sites within the kringle domains 22 . Due to the closed nature of native glu-plasminogen crystallography studies indicate that only the binding domain in kringle one is available for initial binding 23 .…”

Section: Discussionmentioning

confidence: 99%

Exposure of plasminogen and a novel plasminogen receptor, Plg-RKT, on activated human and murine platelets

Whyte

Morrow

Baik

et al. 2021

Blood

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Plasminogen activation rates are enhanced by cell surface binding. We have previously demonstrated that exogenous plasminogen binds to phosphatidylserine-exposing and spread platelets. Platelets contain plasminogen in their α-granules but secretion of plasminogen from platelets has not been studied. Recently, a novel transmembrane lysine-dependent plasminogen receptor, Plg-RKT, has been described on macrophages. Here, we analyzed the pool of plasminogen in platelets and examined whether platelets express Plg-RKT. Plasminogen content of the supernatant of resting and collagen/thrombin-stimulated platelets was similar. Pre-treatment with the lysine analogue, εACA, significantly increased platelet-derived plasminogen (0.33 nmol/108 plts vs. 0.08 nmol/108 plts) in the stimulated supernatant, indicating a lysine-dependent mechanism of membrane retention. Lysine-dependent, platelet-derived plasminogen retention on thrombin and convulxin activated human platelets was confirmed by flow cytometry. Platelets initiated fibrinolytic activity in fluorescently labelled plasminogen-deficient clots and in turbidimetric clot lysis assays. A 17 kDa band, consistent with Plg-RKT, was detected in the platelet membrane fraction by Western blotting. Confocal microscopy of stimulated platelets revealed Plg-RKT co-localized with platelet-derived plasminogen on the activated platelet membrane. Plasminogen exposure was significantly attenuated in thrombin and convulxin stimulated platelets from Plg-RKT-/- mice compared to Plg-RKT+/+ littermates. Membrane exposure of Plg-RKT was not dependent on plasminogen, as similar levels of the receptor were detected in plasminogen-/- platelets. These data highlight Plg-RKT as a novel plasminogen receptor in human and murine platelets. We show for the first time that platelet-derived plasminogen is retained on the activated platelet membrane and drives local fibrinolysis, by enhancing cell-surface mediated plasminogen activation.

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“…In HAE-PLG, it is known that the variant in the PLG gene leads to an amino acid exchange in the kringle 3 domain of plasminogen. The kringle 3 domain serves for attachment of plasminogen on the cell surface [21,22]. The consequence might be an increased activation of the fibrinolytic system with subsequent formation of plasmin, activation of KKS, and increased production of bradykinin [8].…”

Section: Discussionmentioning

confidence: 99%

Treatment of patients with hereditary angioedema with the c.988A>G (p.Lys330Glu) variant in the plasminogen gene

Bork

Wulff

Witzke

et al. 2020

Orphanet J Rare Dis

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Background Hereditary angioedema (HAE) in patients with normal C1 inhibitor (C1-INH) and the c.988A > G (p.Lys330Glu; p.K330E) variant in the plasminogen gene (HAE-PLG) is associated with skin swellings, abdominal pain attacks, and the risk of asphyxiation due to upper airway obstruction. Aim of this observational, retrospective study is to report about the efficacy of various treatments for acute attacks and long-term prophylaxis. Results The study included 111 patients with HAE-PLG. Thirteen patients were treated with icatibant for 201 acute swelling attacks. The mean duration of the treated attacks (mean 4.3 h; standard deviation [SD] 2.6 h) was significantly shorter than that of the previous 149 untreated attacks (mean 44.7 h; SD 28.6 h, p < 0.0001). Twelve patients were treated with plasma-derived C1-INH for 74 acute swelling attacks. The duration of the treated attacks (mean 31.5 h; SD 18.6 h) was significantly shorter than that of the previous 129 untreated in the same patients (mean 48.2 h; SD 32.5 h, p < 0.0001). Corticosteroids alone showed good response in 61/268 attacks (8 patients), low response in 82/268 attacks (7 patients), and no response in 125/268 attacks (26 patients). Corticosteroids combined with antihistamines showed good response in 13/309 attacks (4 patients), low response in 150/309 attacks (7 patients), and no response in 146/309 attacks (17 patients). Antihistamines alone were ineffective in all 37 attacks of 5 patients. In 2 patients with imminent asphyxiation due to tongue swelling and partial obstruction of the upper airways fresh frozen plasma was used without clinical response. The mean reduction in attack frequency was 46.3% under progestins (6 patients), 93.9% under tranexamic acid (3 patients) and 83.3% under danazol (3 patients). Conclusions For patients with HAE-PLG various treatment options are available, which completely or at least partially reduce attack duration or attack frequency.

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The cell-binding domains of plasminogen and their function in plasma.

Cited by 129 publications

References 39 publications

Wound Fluid from Venous Leg Ulcers Degrades Plasminogen and Reduces Plasmin Generation by Keratinocytes

Wound Fluid from Venous Leg Ulcers Degrades Plasminogen and Reduces Plasmin Generation by Keratinocytes

Exposure of plasminogen and a novel plasminogen receptor, Plg-RKT, on activated human and murine platelets

Treatment of patients with hereditary angioedema with the c.988A>G (p.Lys330Glu) variant in the plasminogen gene

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