Reversible interactions between plasminogen activators and plasminogen activator inhibitor-1

Mimuro, Jun; Kaneko, Munekiyo; Murakami, Toshinobu; Matsuda, Michio; Sakata, Yoichi

doi:10.1016/0167-4838(92)90095-u

Cited by 22 publications

(15 citation statements)

References 25 publications

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“…We began by examining the contribution of amino acids 105-110 in the kringle, which have been implicated previously in binding to heparin and PAI-1. 40,50,54,55 This portion of the kringle is found in apposition to the GFD in several of the published NMR structures, consistent with the flexibility of the ATF. To examine the involvement of this region within the full-length molecule, we generated a scuPA-kringle variant (designated scuPA-Lys105-110Ala) in which each of the charged amino acids implicated in heparin binding were mutated to alanine.…”

Section: Identification Of Kringle Epitopes Involved In Stabilizationmentioning

confidence: 55%

The kringle stabilizes urokinase binding to the urokinase receptor

Bdeir

Kuo

Sachais

et al. 2003

Blood

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The structural basis of the interaction between single-chain urokinase-type plasminogen activator (scuPA) and its receptor (uPAR) is incompletely defined. Several observations indicated the kringle facilitates the binding of uPA to uPAR. A scuPA variant lacking the kringle (⌬K-scuPA) bound to soluble uPAR (suPAR) with the similar "on-rate" but with a faster "off-rate" than wild-type (WT)-scuPA. Binding of ⌬K-scuPA, but not WT-scuPA, to suPAR was comparably inhibited by its growth factor domain (GFD) and amino-terminal fragment (ATF).ATF and WT-scuPA, but not GFD, scuPA lacking the GFD (⌬GFD-scuPA), or ⌬K-scuPA reconstituted the isolated domains of uPAR. ATF completely inhibited the enzymatic activity of WT-scuPAsuPAR unlike comparable concentrations of GFD. Variants containing mutations that alter the charge, length, or flexibility of linker sequence (residues 43-49) between the GFD and the kringle displayed a lower affinity for uPAR, were unable to reconstitute uPAR domains, and their binding to uPAR was inhibited by GFD in the same manner as ⌬K-scuPA. IntroductionUrokinase-type plasminogen activator (uPA) has been implicated in diverse physiologic and pathophysiologic processes that involve cell adhesion, fibrinolysis, and signal transduction. 1-3 Several of these processes are mediated by the catalytic activity of the molecule, 4 while others involve the participation of the uPA receptor (uPAR) 1,[5][6][7][8] or other cell surface molecules. 8,[9][10][11] uPA is expressed as a single-chain molecule (scuPA) composed of an N-terminal fragment (ATF; amino acids 1-135) and a protease domain (amino acids 136-411), also known as low molecular weight uPA (LMW-uPA). The amino-terminal fragment (ATF) is itself composed of 2 independent domains, the amino-terminal growth factor-like domain (GFD; amino acids 1-43), which is known to bind to the uPA receptor, and a single kringle (K; amino acids 47-135), the function of which is uncertain. [12][13][14][15][16][17] scuPA expresses plasminogen activator activity when converted to a 2-chain molecule (tcuPA) by plasmin 18 or as a single-chain molecule when bound to its receptor. [19][20][21][22] The mature urokinase receptor (uPAR) is a 283-amino acid glycolipid-anchored protein composed of 3 partial repeat domains. 5,6,23 Cooperation among the 3 domains is required to optimize scuPA binding and activation. [24][25][26] Binding of scuPA is inhibited by peptides that cross-link residues Arg53 and Leu66 in domain I and His251 in domain III of uPAR, respectively, 27,28 or by mutations in a region of domain II, which has been implicated in interdomain cooperativity. 26 There is compelling evidence to indicate that scuPA binds to uPAR through its GFD. [28][29][30][31][32][33][34] However, the potential involvement of other sites in uPA in receptor binding has not been studied in detail.Evidence favoring the existence of such auxiliary sites comes from studies in which uPA-induced, uPAR-mediated adhesion to vitronectin (Vn) and other integrin ligands has been examined using purif...

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Section: Identification Of Kringle Epitopes Involved In Stabilizationmentioning

confidence: 55%

The kringle stabilizes urokinase binding to the urokinase receptor

Bdeir

Kuo

Sachais

et al. 2003

Blood

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“…Therefore, we can easily recognize the cancer cell as uPA-positive or uPA-negative with the AMeX method and our data are thought to be very reliable. Recently, many reports about the correlation between uPA and its inhibitors (plasminogen inhibitor-1, PAI-1) have been seen [33]. In breast cancer, tumor cells synthesize PAI-1, which is capable of blocking the enzymatic activity of uPA.…”

Section: Discussionmentioning

confidence: 99%

Association of Immunohistochemical Detection of Urokinase-Type Plasminogen Activator with Metastasis and Prognosis in Colorectal Cancer

Sato

Nishimura²,

Yonemura³

et al. 1995

Oncology

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We evaluated urokinase-type plasminogen activator (uPA) expression with immunohistochemistry in 90 cases of colorectal cancer and compared it with the clinicopathological findings. Patients who had cancer cells which were stained intensively relative to the background were recognized as uPA-posi-tive patients. The uPA-positive rate was 36.7% (33/90) in total cases. There was a significant correlation between uPA expression and lymph node metastasis. A significant correlation was also seen between uPA expression and liver metastasis. Prognosis was poorer in the uPA-positive patients than in the uPA-negative patients. Therefore, uPA may be a good predictor of metastasis and prognosis.

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“…In addition, interactions between PAI-1 and uPA may modify activation pathways involving uPA through prolonging cellular exposure to the uPA KD or altering uPA conformation (35,36). Association of PAI-1 and uPA involves the PD of uPA, without a requirement for the KD, and induces internalization of uPA through the low-density lipoprotein receptor-related protein/␣ 2 -macroglobulin receptor (7,37). The high levels of immunoreactive uPA found in the lungs after LPS exposure or in the setting of pneumonia, although inactive in terms of fibrinolysis, could still have potent effects on the activation of neutrophils, and perhaps of other pulmonary cell populations, such as alveolar macrophages, that are involved in inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

Involvement of the Urokinase Kringle Domain in Lipopolysaccharide-Induced Acute Lung Injury

Wang

Bdeir

Yarovoi

et al. 2006

The Journal of Immunology

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Urokinase plasminogen activator (uPA) plays a major role in fibrinolytic processes and also can potentiate LPS-induced neutrophil activation through interactions with its kringle domain (KD). To investigate the role of the uPA KD in modulating acute inflammatory processes in vivo, we cloned and then developed Abs to the murine uPA KD. Increased pulmonary expression of uPA and the uPA KD was present in the lungs after LPS exposure. Administration of anti-kringle Abs diminished LPS-induced up-regulation of uPA and uPA KD in the lungs, and also decreased the severity of LPS-induced acute lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, histology, and lung IL-6, MIP-2, and TNF-α cytokine levels. These proinflammatory effects of the uPA KD appeared to be mediated through activation of Akt and NF-κB. The present studies indicate that the uPA KD plays a major role in the development of TLR4-mediated acute inflammatory processes, including lung injury. Blockade of the uPA KD may prevent the development or ameliorate the severity of acute lung injury induced through TLR4-dependent mechanisms, such as would occur in the setting of Gram-negative pulmonary or systemic infection.

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Reversible interactions between plasminogen activators and plasminogen activator inhibitor-1

Cited by 22 publications

References 25 publications

The kringle stabilizes urokinase binding to the urokinase receptor

The kringle stabilizes urokinase binding to the urokinase receptor

Association of Immunohistochemical Detection of Urokinase-Type Plasminogen Activator with Metastasis and Prognosis in Colorectal Cancer

Involvement of the Urokinase Kringle Domain in Lipopolysaccharide-Induced Acute Lung Injury

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