Cleavage of urokinase receptor regulates its interaction with integrins in thyroid cells (original) (raw)
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Cancer research, 1998
We studied the urokinase-type plasminogen activator (uPA) receptor (uPA-R) in normal and neoplastic human thyroid cells. It has recently been shown that cleaved forms of uPA-R display an extremely strong chemotactic activity. Normal human thyroid TAD-2 cells express the intact form of the uPA-R and a truncated form lacking the uPA-binding domain on their surface, in a similar manner to tumor thyroid cell lines. However, in tumor thyroid cell lines, the amount of the truncated form is variable: high in papillary carcinoma cells, very low in follicular carcinoma cells, and not detectable in anaplastic carcinoma cells. Similar studies on primary cell cultures confirm the presence of the truncated form of uPA-R in normal and in papillary carcinoma cells and its partial or total loss in follicular carcinoma cells. The presence of truncated uPA-R correlates to uPA secretion, except in papillary carcinoma cells, which express the truncated form of uPA-R but do not release uPA. uPA-R is als...
Urokinase-type plasminogen-activator and normal thyroid cell adhesion to the extracellular matrix
Biochimie, 1999
The urokinase-type plasminogen activator receptor (uPA-R) focuses the proteolytic activity of its ligand, the urokinase-type plasminogen activator (uPA), on the cell surface, and can also act as an adhesion receptor for vitronectin (VTN). uPA increases uPA-R affinity for VTN and is also able to cleave its receptor. We have previously shown that uPA-R is involved in the adhesion of normal
FEBS Letters, 1992
Five rat thyroid cell lines were tested for the expression of the cell surface receptor for urokinase type plasminogen activator (uPA). All tested lines were found to bind uPA. but transformed I-SG and Ki-Mol cells, which are also high uPA producers, bound at least ten times more uPA. as compared to non-producers. 'normal' TL5 cells. Moreover, it was possible to remove membrane-bound uPA by treating the cells with phospha-tidylit~ositol-specific phopholipase C. suggesting that rat uPAR, like its human counterpart, is link~xl to the membrane by a ~luco~yl-phosphatidylinositol anchor. The specificity of the binding was tested by competition with three different synthetic peptides corresponding to anaino acids 14-37 of human, rat and mouse uPA. The results indicate also that the receptor binding region of rat uPA is located within the growth factor domain of the molecule and that its expression may be dependent on the transformed state of the cells.
Urokinase-type plasminogen activator and its inhibitor in thyroid neoplasms: a cytosol study
Zusammenfassung. Ziel der Studie: Erhöhte Konzentrationen des Urokinase-Typ Plasminogen-Aktivators (uPA) und seines Inhibitors (PAI 1) sind bei einer Reihe von malignen Erkrankungen mit einer schlechten Prognose verbunden. Entsprechend immunhistochemischer Messungen werden uPA und PAI 1 von den meisten Schilddrüsenkarzinomen exprimiert. Es konnte allerdings kein Zusammenhang zwischen der Expression dieser Substanzen und klinisch-pathologischen Parametern gefunden werden. Das Ziel der vorliegenden Studie war es, die klinische Relevanz der Expression von uPA und PAI 1 bei Patienten mit Schilddrüsenkarzinom zu untersuchen.
European Journal of Cancer, 2006
Thyroid tumours Plasminogen activators Plasminogen activator inhibitors Urokinase plasminogen activator receptor Human A B S T R A C T We characterised the expression of the plasminogen activators (uPA and tPA), the uPA receptor (uPAR) and the PAs inhibitors (PAI-1 and PAI-2) in human thyroid cell lines derived from normal thyroid, follicular adenoma, follicular, papillary and anaplastic carcinomas. Urokinase PA activity was detected in the supernatant of normal thyrocytes and augmented in those of all tumour cells. Quantitative RT-PCR analysis showed that uPA, uPAR and PAI-1 mRNAs increased in all carcinoma cells. Similar results were found in 13 papillary thyroid carcinoma (PTC) tissues which were mirrored in Western blot experiments.
Urokinase-type plasminogen activator up-regulates the expression of its cellular receptor
Febs Letters, 2000
The expression of the receptor for the urokinase-type plasminogen activator (uPAR) can be regulated by several hormones, cytokines, tumor promoters, etc. Recently, it has been reported that uPAR is capable of transducing signals, even though it is lacking a transmembrane domain and a cytoplasmatic tail. We now report that uPAR cell surface expression can be positively regulated by its ligand, uPA, in thyroid cells. The effect of uPA is independent of its proteolytic activity, since inactivated uPA or its aminoterminal fragment have the same effects of the active enzyme. The increase of uPAR on the cell surface correlates with an increase of specific uPAR mRNA. Finally, uPA up-regulates uPAR expression also in other cell lines of different type and origin, thus suggesting that the regulatory role of uPA on uPAR expression is not restricted to thyroid cells, but it occurs in different tissues, both normal and tumoral. ß
Integrin-dependent induction of functional urokinase receptors in primary T lymphocytes
Journal of Clinical …, 1996
In order to reach the sites of inflammation, lymphocytes leave the bloodstream and migrate into peripheral tissues, in a process involving integrin-mediated adhesion to the vascular endothelium, followed by transmigration across the endothelial barrier and through the underlying interstitial matrix. We have investigated the role of the plasminogen activator/plasmin system in normal T cell migration. Receptors for urokinase plasminogen activator (uPAR) were not expressed in resting T lymphocytes, but could be efficiently induced at the mRNA and protein level by coclustering of the antigen receptor complex and  1 or  2 integrins, through a signalling pathway involving both protein kinase C activation and an increase in intracellular cyclic AMP. Catalytic activation of plasminogen by uPAR-expressing T cells promoted their migration through an extracellular matrix in vitro. Plasmin-induced invasion was inhibited by plasmin-and urokinase inhibitors and by anti-uPAR antibodies. Finally, cytofluorimetric and immunohistochemical analysis of primary human tumor specimens showed the presence of uPAR positive infiltrating T cells in vivo. Collectively, these findings suggest that plasminogen activation may play a role in lymphocyte migration in vivo, and that integrin-dependent expression of membrane-associated endopeptidases could represent an additional step in the regulated process of leukocyte transmigration.
2007
Purpose: Higher levels of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) are linked to the poor prognosis in a variety of malignances. uPA and PAI-1 were expressed in most thyroid carcinomas, as had been measured immunohistochemically. However, no relationship between their expression and clinicopathological parameters were described. Aim of the present study was to investigate the expression and clinical relevance of uPA and PAI-1 in thyroid cancer. Patients and methods: uPA and PAI-1 in paired cytosol samples of thyroid tumor and normal tissue were determined in 23 patients using enzyme-linked immunosorbent assay and correlated to the known prognostic features. Results: Both uPA and PAI-1 concentrations were significantly higher in malignant thyroid tumors (uPA=1.342± ; 2.944 and PAI-1=17.615± ; 31.933 ng/mg protein) than in normal tissue (uPA=0.002± ; 0.009, P=0, 011 and PAI-1=2.333± ; 0.338 ng/mg protein, P=0, 001) with positive correlation of the two prote...
International Journal of Molecular Sciences
Increased expression of the urokinase-type plasminogen activator (uPA) system is associated with tumor invasion, neo-angiogenesis, and metastatic spread, and has been shown to positively correlate with a poor prognosis in several cancer types, including thyroid carcinomas. In recent years, several uPA inhibitors were found to have anticancer effects in preclinical studies and in some phase II clinical trials, which prompted us to evaluate uPA as a potential therapeutic target for the treatment of patients affected by the most aggressive form of thyroid cancer, the anaplastic thyroid carcinoma (ATC). In this study, we evaluated the in vitro and in vivo effects of WX-340, a highly specific and selective uPA inhibitor, on two ATC-derived cell lines, CAL-62 and BHT-101. The results obtained indicated that WX-340 was able to reduce cell adhesion and invasiveness in a dose-dependent manner in both cell lines. In addition, WX-340 increased uPA receptor (uPAR) protein levels without affecti...