Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasma membrane and lysosomal proteases, gamma-glutamyl transferase and extracellular matrix proteases were investigated by qualitative cytochemical means in the mature placenta of mice, rats, guinea-pigs and marmosets. These studies revealed similarities, which concerned primarily the lysosomal proteases in different structures of the placenta and all proteases and gamma-glutamyl transferases in the zone of placental shedding. However, species differences predominated. They were observed especially for amino-peptidase A and M, dipeptidyl peptidase IV and gamma-glutamyl transferase in the plasma membranes and extracellular matrix of the placental barrier and decidual cells of all species and the cells of the basal zone in rats and mice. Plasma membrane and extracellular matrix proteases in other parts of the placenta, e.g. the placenta stem of guinea-pigs and basal plate, amniotic and chorionic plate of marmosets occurred only in these species. Elastase substrates hydrolysing endopeptidase I and kallikrein-, thrombin-, plasmin-, plasminogen- and cathepsin B substrates hydrolysing endopeptidase II were not observed in any of these species. A general comparison of the species revealed similarities for the mouse, rat and guinea-pig placental barrier, but not for that of marmosets. The proteases of this zone in the marmoset placenta are more similar to the human situation, but do not correspond to it completely.
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PMID:Protease cytochemistry in the murine rodent, guinea-pig and marmoset placenta. 287 14

Adenosine deaminase (ADA) is expressed intracellularly by all cells, but in some tissues, it is also associated with the cell surface multifunctional glycoprotein CD26/dipeptidyl peptidase IV. By modulating extracellular adenosine, this "ecto-ADA" may regulate adenosine receptor signaling implicated in various cellular functions. CD26 is expressed on the surface of human prostate cancer 1-LN cells acting as a receptor for plasminogen (Pg). Since ADA and Pg bind to CD26 at distinct but nearby sites, we investigated a possible interaction between these two proteins on the surface of 1-LN cells. Human ADA binds to CD26 on the surface 1-LN cells and immobilized CD26 isolated from the same cells with similar affinity. In both cases, ADA binding is diminished by mutation of ADA residues known to interact with CD26. ADA was also found to bind Pg 2 in the absence of CD26 via the Pg kringle 4 (K4) domain. In the presence of 1-LN cells or immobilized CD26, exogenous ADA enhances conversion of Pg 2 to plasmin by 1-LN endogenous urinary plasminogen activator (u-PA), as well as by added tissue Pg Activator (t-PA), suggesting that ADA and Pg bind simultaneously to CD26 in a ternary complex that stimulates the Pg activation by its physiologic activators. Consistent with this, in melanoma A375 cells that bind Pg, but do not express CD26, the rate of Pg activation was not affected by ADA. Thus, ADA may be a factor regulating events in prostate cancer cells that occur when Pg binds to the cell surface and is activated.
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PMID:Cell surface adenosine deaminase binds and stimulates plasminogen activation on 1-LN human prostate cancer cells. 1501 24

Circulating antiplasmin-cleaving enzyme (APCE), a prolyl-specific serine proteinase, is essentially identical to membrane-inserted fibroblast activation protein (FAP) that is transiently expressed during epithelial-derived cancer growth. Human precursive alpha(2)-antiplasmin (Met-alpha(2)AP), the only known physiologic substrate for APCE, is cleaved N-terminally to Asn-alpha(2)AP that is rapidly cross-linked to fibrin and protects it from digestion by plasmin. Identifying a specific inhibitor of APCE/FAP continues to be intensely pursued. Recombinant FAP cleavage of peptide libraries of short amino acid sequences surrounding the scissile bond, -Pro(12)-Asn(13)-, indicated that P2 Gly and P1 Pro are required, just as we found for APCE. We examined cleavage of P4-P4' peptides, using 19 amino acid substitutions at each position and selected ones in P8-P5. K(m) values determined for peptide substrates showed that P7 Arg has the highest affinity for APCE. Peptide cleavage rate increased with Arg in P6 rather than P5 or native P7. Placing Arg in P4 or P8 reduced cleavage rates dramatically. Cleavage of substrates with extended peptide sequences before or after the scissile bond showed endopeptidase to be superior to dipeptidase activity for APCE. A substrate analogue inhibitor, Phe-Arg-(8-amino-3,6-dioxaoctanoic acid)-Gly-[r]-fluoropyrrolidide, inhibited APCE with a K(i) of 54 microM but not dipeptidyl peptidase IV even at 2 mM. The inhibitor also blocked cleavage of Met-alpha(2)AP with an IC(50) of 91 microM. Replacing Arg with Gly at the same distance from fluoropyrrolidide as P7 Arg is from P1 Pro reduced its inhibition of APCE approximately 10-fold. Results indicate that Arg at P5, P6, or P7 distances from P1 enhances affinity and efficiency of substrates or inhibitors toward APCE or FAP.
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PMID:Using substrate specificity of antiplasmin-cleaving enzyme for fibroblast activation protein inhibitor design. 1940 13

The CC chemokine CCL14a is constitutively expressed in a large variety of tissues and its inactive proform CCL14a(1-74) circulates in high concentrations in plasma. CCL14a(1-74) is converted into CCL14a(9-74) by the proteases urokinase-type plasminogen activator and plasmin and is a highly active agonist for the chemokine receptors CCR1 and CCR5. In this study, a new CCL14a analog, CCL14a(12-74), was isolated from blood filtrate. To elucidate the functional role of the N terminus, a panel of N-terminally truncated CCL14a analogs were tested on the receptors CCR1 to CCR5 and on the human cytomegalovirus (HCMV)-encoded chemokine receptor US28. The rank order of binding affinity to these receptors and of the activation of CCR1 and CCR5-mediated intracellular Ca(2+) concentration mobilization is CCL14a(6-74)<(7-74)<(8-74)<<(9-74) = (10-74)>>(11-74)>>(12-74). The almost identical affinities of CCL14a(7-74), CCL14a(9-74), and CCL14a(10-74) for the US28 receptor and the inhibition of US28-mediated HIV infection of 293T cells by all of the N-terminally truncated CCL14a analogs support the promiscuous nature of the viral chemokine receptor US28. In high concentrations, CCL14a(12-74) did reveal antagonistic activity on intracellular Ca(2+) concentration mobilization in CCR1- and CCR5-transfected cells, which suggests that truncation of Tyr(11) might be of significance for an efficient inactivation of CCL14a. A putative inactivation pathway of CCL14a(9-74) to CCL14a(12-74) may involve the dipeptidase CD26/dipeptidyl peptidase IV (DPPIV), which generates CCL14a(11-74), and the metalloprotease aminopeptidase N (CD13), which displays the capacity to generate CCL14a(12-74) from CCL14a(11-74). Our results suggest that the activity of CCL14a might be regulated by stringent proteolytic activation and inactivation steps.
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PMID:Significance of N-terminal proteolysis of CCL14a to activity on the chemokine receptors CCR1 and CCR5 and the human cytomegalovirus-encoded chemokine receptor US28. 1955 44

The chemokine decoy receptor D6 controls inflammatory responses by selective recognition and degradation of most CCR1 to CCR5 agonistic ligands. CCL14 is a homeostatic chemokine present at high concentrations in the serum with a weak agonist activity on CCR1. Under inflammatory conditions, plasmin and UPA-mediated truncation of 8 amino acids generates the potent CCR1/CCR3/CCR5 isoform CCL14(9-74), which is further processed and inactivated by dipeptidyl peptidase IV/CD26 that generates CCL14(11-74). Here we report that D6 efficiently binds both CCL14 and its truncated isoforms. Like other D6 ligands, the biologically active CCL14(9-74) induces adaptive up-regulation of D6 expression on the cell membrane and is rapidly and efficiently degraded. In contrast, the D6-mediated degradation of the biologically inactive isoforms CCL14(1-74) and CCL14(11-74) is very inefficient. Thus, D6 cooperates with CD26 in the negative regulation of CCL14 by the selective degradation of its biologically active isoform. Analysis of a panel of CC chemokines and their truncated isoforms revealed that D6-mediated chemokine degradation does not correlate with binding affinity. Conversely, degradation efficiency is positively correlated with D6 adaptive up-regulation. Sequence analysis indicated that a proline residue in position 2 of D6 ligands is dispensable for binding but crucial for D6 adaptive up-regulation and efficient degradation.
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PMID:Recognition versus adaptive up-regulation and degradation of CC chemokines by the chemokine decoy receptor D6 are determined by their N-terminal sequence. 1963 87