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)

Cellular proteases are those proteases that are localized in the cytoplasm and on the cell surface, but not those secreted into the extracellular matrix. Proteases localized on the cell surface play a specific role in the invasion process of malignant tumor cells. These are activated by a relatively complicated cascade in which different cathepsins, the plasminogen activator system, plasmin, and the matrix metalloproteinases, including the membrane-type matrix metalloproteinases, play a major role. This article places emphasis on the biologic function and oncologic significance of cathepsins B and L, as well as on the urokinase plasminogen activator and the membrane-type matrix metalloproteinases localized on the cell surface. Recent investigations on these factors revealed that they are dependent on each other, such that the upregulation or downregulation also causes alterations in the regulation of the other factors. This fact alone elucidates the complexity of this system. Moreover, there is growing evidence that other proteases hitherto known to have other functions, e.g. as signal proteases in the immunologic system, may be important for invasion provesses. To provide an example of this, we describe the invasive potential of aminopeptidase N (APN/CD13). These recent results, which shed light on the role of further proteases in invasion processes, clearly show the complexity of this proteolytic system. Against this biologic background, it seems not to be promising to establish single proteases as distinct parameters for the prognosis of the metastatic potential of malignant tumors.
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PMID:[Cellular proteases and invasion]. 1121 51

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

Chemokines are important proteins involved in the regulation of directed leukocyte migration during inflammation and the homeostatic homing of immune cells. In addition, they play a role in angiogenesis, hematopoiesis, organogenesis, tumor growth and metastasis. Therefore, the chemokine/chemokine receptor network is highly complex and needs to be tightly controlled. An important mechanism of fine-tuning chemokine activity and reducing its apparent redundancy is post-translational modification (PTM) of chemokines and their receptors. Under inflammatory conditions, enzymes such as matrix metalloproteinases (MMPs), plasmin, CD13, CD26, and peptidylarginine deiminases (PADs) and protein-modifying agents, such as peroxynitrite, are upregulated and released and may provoke truncation, degradation, nitration or citrullination of chemokines. Most modified chemokines show altered biological activity. This review reports how PTMs influence the biological functions of chemokines, with special attention for the impact beyond chemotaxis.
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PMID:How post-translational modifications influence the biological activity of chemokines. 2990 73