Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hepatocyte growth factor (HGF) is a multifunctional cytokine that is produced as latent scHGF (single chain HGF). Various proteases reportedly cleave scHGF to generate the active two-chain form (HGF), including u-PA (urokinase-type plasminogen activator), t-PA (tissue-type plasminogen activator), kallikrein, Factor XIa, Factor XIIa, HGF activator and matriptase. Considerable evidence indicates that, in vivo, u-PA activates scHGF in the liver; however, the in vivo results have not been uniformly supported by in vitro experiments. We now report that cleavage of scHGF by high-molecular-mass u-PA (abbreviated u-PA throughout) is sensitive to ionic strength. scHGF cleavage by u-PA was accelerated as the ionic strength was decreased. This result was equivalent irrespective of whether the predominant anion was chloride or acetate. Lmw-u-PA (low-molecular-mass u-PA) was ineffective at cleaving scHGF, regardless of ionic strength. Although scHGF shares homology with plasminogen, EACA (-amino-caproic acid) did not regulate u-PA-mediated scHGF cleavage. Soluble HGF receptor (MET) and soluble u-PAR (u-PA receptor) inhibited the scHGF cleavage. These results support a model in which the ability of u-PA to activate scHGF in vivo may be highly dependent on local conditions within the extracellular space.
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PMID:Activation of hepatocyte growth factor by urokinase-type plasminogen activator is ionic strength-dependent. 1586 63

Hepsin, a type II transmembrane serine protease, is strongly up-regulated in prostate cancer. Hepsin overexpression in a mouse prostate cancer model resulted in tumor progression and metastasis, associated with basement membrane disorganization. We investigated whether hepsin enzymatic activity was linked to the basement membrane defects by examining its ability to initiate the plasminogen/plasmin proteolytic pathway. Because plasminogen is not processed by hepsin, we investigated the upstream activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator. Enzymatic assays with a recombinant soluble form of hepsin demonstrated that hepsin did not cleave pro-tissue-type plasminogen activator but efficiently converted pro-uPA into high molecular weight uPA by cleavage at the Lys158-Ile159 (P1-P1') peptide bond. uPA generated by hepsin displayed enzymatic activity toward small synthetic and macromolecular substrates indistinguishable from uPA produced by plasmin. The catalytic efficiency of pro-uPA activation by hepsin (kcat/Km 4.8 x 10(5) m(-1) s(-1)) was similar to that of plasmin, which is considered the most potent pro-uPA activator and was about 6-fold higher than that of matriptase. Conversion of pro-uPA was also demonstrated with cell surface-expressed full-length hepsin. A stable hepsinoverexpressing LnCaP cell line converted pro-uPA into high molecular weight uPA at a rate of 6.6 +/- 1.9 nm uPA h(-1), which was about 3-fold higher than LnCaP cells expressing lower hepsin levels on their surface. In conclusion, the ability of hepsin to efficiently activate pro-uPA suggests that it may initiate plasmin-mediated proteolytic pathways at the tumor/stroma interface that lead to basement membrane disruption and tumor progression.
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PMID:Pro-urokinase-type plasminogen activator is a substrate for hepsin. 1690 24

The PDGF (platelet-derived growth factor) family members are potent mitogens for cells of mesenchymal origin and serve as important regulators of cell migration, survival, apoptosis and transformation. Tumour-derived PDGF ligands are thought to function in both autocrine and paracrine manners, activating receptors on tumour and surrounding stromal cells. PDGF-C and -D are secreted as latent dimers, unlike PDGF-A and -B. Cleavage of the CUB domain from the PDGF-C and -D dimers is required for their biological activity. At present, little is known about the proteolytic processing of PDGF-C, the rate-limiting step in the regulation of PDGF-C activity. In the present study we show that the breast carcinoma cell line MCF7, engineered to overexpress PDGF-C, produces proteases capable of cleaving PDGF-C to its active form. Increased PDGF-C expression enhances cell proliferation, anchorage-independent cell growth and tumour cell motility by autocrine signalling. In addition, MCF7-produced PDGF-C induces fibroblast cell migration in a paracrine manner. Interestingly, PDGF-C enhances tumour cell invasion in the presence of fibroblasts, suggesting a role for tumour-derived PDGF-C in tumour-stromal interactions. In the present study, we identify tPA (tissue plasminogen activator) and matriptase as major proteases for processing of PDGF-C in MCF7 cells. In in vitro studies, we also show that uPA (urokinase-type plasminogen activator) is able to process PDGF-C. Furthermore, by site-directed mutagenesis, we identify the cleavage site for these proteases in PDGF-C. Lastly, we provide evidence suggesting a two-step proteolytic processing of PDGF-C involving creation of a hemidimer, followed by GFD-D (growth factor domain dimer) generation.
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PMID:Platelet-derived growth factor-C (PDGF-C) activation by serine proteases: implications for breast cancer progression. 2203 41