Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have indicated that cyst fluid of ovarian tumors contains 2 trypsinogen isoenzymes, called tumor-associated trypsinogen-I (TAT-I) and trypsinogen-2 (TAT-2), the levels of which correlate with the degree of malignancy of the tumors. In addition, these cyst fluids contain large amounts of tumor-associated trypsin inhibitor (TATI), which is also expressed in many other human tumors. In the present study we examined the production of TAT-I, TAT-2 and TATI in 9 established tumor-cell lines. TAT-2 was produced by 5 cell lines. Its concentration in the conditioned medium of COLO 205 colon adenocarcinoma cells, K-562 erythroleukemia cells and fibrosarcoma cell lines HT 1080, 8387 and A 9733 was 460 micrograms/l, 9.8 micrograms/l, 21 micrograms/l, 8.8 micrograms/l and 0.24 micrograms/l, respectively. TAT-I was detectable in the conditioned medium of COLO 205 and HT 1080 cells at concentrations of 64 micrograms/l and 0.5 micrograms/l, respectively. TATI was detected only in the media of COLO 205 cells at a concentration of 23 micrograms/l. TAT-2 zymogen was purified from the conditioned medium of COLO 205 and HT 1080 cells by immunoaffinity chromatography. According to its aminoterminal amino acid sequence, a molecular mass of 28 kDa by SDS-PAGE, elution pattern in ion-exchange chromatography and ability to be activated by enteropeptidase, the zymogen is identical to that previously isolated from cyst fluid of ovarian tumors. In addition, we found that TAT-2 secretion could be down-regulated by dexamethasone in HT 1080 cells but not in COLO 205 cells. The abundant production of TAT-2 isoenzyme in different cancer cell lines suggests that it could contribute to the increased proteolytic activity of many human tumors.
 ...
PMID:Human colon carcinoma, fibrosarcoma and leukemia cell lines produce tumor-associated trypsinogen. 199 87

We have recently demonstrated that many cancer cell lines produce a novel trypsinogen isoenzyme called tumor-associated trypsinogen 2 (TAT-2). It was found during a search of the target protease for tumor-associated trypsin inhibitor (TATI). We now show that degradation of subendothelial cell extracellular matrix (ECM) by four different cell lines (COLO 205 colon carcinoma, K-562 erythroleukemia, CAPAN-1 pancreatic carcinoma, and HT 1080 fibrosarcoma) can be partially inhibited by TATI or neutralizing trypsin antibodies. When cells were cultured in serum-free medium on ECM, TATI and trypsin antibodies inhibited the release of immunoreactive fibronectin fragments from ECM by 47-54 and 40%, respectively. Degradation of isotopically labeled ([3H]serine, [3H]proline, and [35S]sulfate) ECM was also significantly prevented by TATI. At its maximum, it exerted a 57% inhibition on the degradation of [3H]serine-labeled ECM. Plasminogen added exogenously to the culture medium further potentiated the proteolysis of ECM. Interestingly, addition of enteropeptidase, an activator of TAT-2, also enhanced cell-mediated proteolysis as assessed by degradation of purified fibronectin coated onto the surface of wells. Immunoblot analysis showed that enteropeptidase-mediated proteolysis generated a pattern of fibronectin fragments similar to that obtained by digestion of purified fibronectin by TAT-2. These results demonstrate the existence of a proteolytic system in tumor cells which is dependent on the activation of TAT-2. We suggest that TAT-2 is involved in a protease cascade-stimulating tumor cell invasion and degradation of extracellular matrix.
 ...
PMID:Tumor-associated trypsin participates in cancer cell-mediated degradation of extracellular matrix. 200 30

Tumour-associated trypsin inhibitor (TATI) is a 6 kDa peptide, which is synthesized at low concentrations by several tumours and cell lines. Very high concentrations of TATI occur in mucinous ovarian tumours. Elevated levels of TATI occur in serum and urine in connection with most types of cancer at advanced stages. In mucinous ovarian cancer up to 85% of all cases have elevated serum levels. Because high levels also occur in early mucinous ovarian cancer TATI appears to be the marker of choice for this tumour. Elevated levels may also occur in nonmalignant disease, especially in patients with severe infections, tissue destruction and pancreatitis. Production of TATI in tumours is associated with expression of two new tumour-associated trypsin(ogen) (TAT) isoenzymes, TAT-1 and -2, TAT-2 being the major form. These enzymes are immunologically similar to trypsinogen-1 and -2, respectively. They activate prourokinase and may therefore trigger the tumour-associated protease cascade contributing to the invasiveness of malignant tumours.
 ...
PMID:Tumour-associated trypsin inhibitor and tumour-associated trypsin. 224 88

In search of the target protease for the tumor-associated trypsin inhibitor TATI we recently identified a trypsin-like protease in cyst fluid of mucinous ovarian tumors (Stenman, U.-H., Koivunen, E., and Vuento, M. (1988) Biol. Chem. Hoppe-Seyler 369, 9-14). We have now purified this protease and demonstrate that it represents isoenzyme forms of trypsinogen, here called tumor-associated trypsin(ogen)s (TAT). The purification procedure comprised batchwise anion exchange chromatography, immunoaffinity chromatography with antibodies to trypsin, and separation of the two isoenzymes by reverse phase chromatography. In sodium dodecyl sulfate (SDS)-gel electrophoresis, the TAT-1 and TAT-2 isoenzymes have relative molecular weights (Mr) of 25,000 and 28,000, respectively, TAT-2 being the major component. The amino-terminal amino acid sequences correspond to those of pancreatic trypsinogen-1 and -2, respectively, and activation of the zymogens results in cleavage of a NH2-terminal activation peptide of 8 residues characteristic of trypsinogen. Isoelectric focusing in the presence of urea gives pI values of about 5 and 4 for TAT-1 and -2, respectively. The substrate specificities of the two TAT isoenzymes are very similar to, but not identical with, those of trypsin-1 and trypsin-2, respectively, suggesting slight differences in substrate binding site. TAT was found to be an efficient activator of pro-urokinase. Hence, TAT could take part in the protease cascade associated with tumor invasion.
 ...
PMID:Human ovarian tumor-associated trypsin. Its purification and characterization from mucinous cyst fluid and identification as an activator of pro-urokinase. 250 10

Various human cancer cells express tumor-associated trypsinogen-2 (TAT-2), which can efficiently activate matrix metalloproteinases (MMPs) in vitro. MMP-2 and MMP-9 are particularly associated with the invasive malignant potential of several tumors. To investigate the role of TAT-2 in tumor invasion, we overexpressed TAT-2 in two malignant human squamous cell carcinoma cell lines of tongue and in non-malignant human papilloma virus transformed gingival keratinocytes. The TAT-2 overexpression significantly increased the levels of active MMP-9 in the most malignant cell line. TAT-2-transfected cells intravasated (invaded blood vessels) up to 60% more efficiently than did the control cells in an in vivo chick embryo chorioallantoic membrane invasion model. This increased intravasation was almost completely abolished by a specific tumor-associated trypsin inhibitor (TATI). These results indicate that TAT-2 has a role in the invasive growth of tumors, either alone or in cascade with gelatinases, especially by generating active MMP-9.
 ...
PMID:MMP-9 activation by tumor trypsin-2 enhances in vivo invasion of human tongue carcinoma cells. 1245 97

This study led to the development of monoclonal antibodies and time-resolved immunofluorometric methods recognizing human trypsinogen-1 and -2, respectively. Using these methods in normal sera the concentration of trypsinogen-1 was found to be higher than that of trypsinogen-2. However, in acute pancreatitis the concentration of serum trypsinogen-2 was 50-fold higher than in controls, whereas the difference in trypsinogen-1 concentration was only 15-fold. Serum samples from patients who had undergone pancreatoduodenectomy contained trypsinogen-2, while trypsinogen-1 was detected in only one of nine samples. Furthermore, in human ovarian cyst fluids tumor-associated trypsinogen-2 (TAT-2) is the predominant isoenzyme and in mucinous cyst fluids the levels of TAT-2 were associated with malignancy. These results suggest that (i) trypsinogen-2 could be used as a diagnostic marker for acute pancreatitis, (ii) its expression is not restricted to the pancreas, and (iii) TAT could be involved in ovarian tumor dissemination and breakage of tissue barriers. In ion exchange chromatography, isoelectric variants of the trypsinogen isoenzymes were seen. Mass spectrometric analysis of these revealed that pancreatic trypsinogens are sulfated at tyrosine 154 (Tyr154), whereas TAT-2 from a colon carcinoma cell line is not. Tyr154 is located within the primary substrate binding pocket of trypsin. Thus, Tyr154 sulfation is likely to influence substrate binding. The previously known differences in charge and substrate binding between pancreatic and tumor-associated trypsinogens are suggested to be caused by sulfation of Tyr154 in pancreatic trypsinogens.
 ...
PMID:Human trypsinogens in the pancreas and in cancer. 2016 5