Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane binding of urokinase type plasminogen activator (u-PA) is thought to play a pivotal role in connective tissue remodeling and invasive processes. We compare the ability of different matrix-metalloproteinases involved in connective tissue turnover to cleave pro-urokinase type plasminogen activator between the catalytic domain and the receptor binding part to investigate a potential role for matrix-metalloproteinases in the regulation of membrane-associated proteolytic activity. We employed several forms of human stromelysin-1 (full length, C-truncated, and recombinant catalytic domain), rabbit C-truncated stromelysin-1, the human gelatinases A and B and the human catalytic domain of neutrophil collagenase. The gelatinases and the collagenase did not separate the receptor binding domain of pro-urokinase type plasminogen activator from the catalytic domain, whereas all stromelysin-1 forms cleaved the glutamic acid 143-leucine 144 bond of pro-urokinase type plasminogen activator. This reaction could be inhibited by specific inhibitors of matrix metalloproteinases and was not affected by inhibitors of serine proteinases. The M(r) 31000 cleavage product with leucine 144 as N-terminus displayed no proteolytic activity towards the pro-urokinase type plasminogen activator substrate pyroGlu-Gly-Arg-pNA-HCI (S2444), but it could be activated by an additional treatment with plasmin. Comparison between full length stromelysin-1 and its C-truncated forms, showed that both exhibited the same cleavage properties towards pro-urokinase type plasminogen activator. Thus, the cleavage of pro-urokinase type plasminogen activator by stromelysin-1 is not influenced by the presence or absence of the C-terminal domain. The recombinant catalytic domain of MMP-3 generated pro-urokinase type plasminogen activator, whereas incubation of pro-urokinase type plasminogen activator with the native forms of human or rabbit stromelysin-1 led to a moderate activation of pro-uPA due to an additional cleavage that is catalyzed by a serine proteinase.
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PMID:The cleavage of pro-urokinase type plasminogen activator by stromelysin-1. 980 93

The role of extracellular proteolysis in innate and adaptive immunity and the interplay between cytokines, chemokines and proteinases are gradually becoming recognized as critical factors in autoimmune processes. Many of the involved proteinases, including those of the plasminogen activator and matrix metalloproteinase cascades, and also several cytokines and chemokines, are glycoproteins. The stability, interactions with inhibitors or receptors, and activities of these molecules are fine-controlled by glycosylation. We studied gelatinase B or matrix metalloproteinase-9 (MMP-9) as a glycosylated enzyme involved in autoimmunity. In the joints of rheumatoid arthritis patients, CXC chemokines, such as interleukin-8/CXCL8, recruit and activate neutrophils to secrete prestored neutrophil collagenase/MMP-8 and gelatinase B/MMP-9. Gelatinase B potentiates interleukin-8 at least tenfold and thus enhances neutrophil and lymphocyte influxes to the joints. When cartilage collagen type II is cleaved at a unique site by one of several collagenases (MMP-1, MMP-8 or MMP-13), it becomes a substrate of gelatinase B. Human gelatinase B cleaves the resulting two large collagen fragments into at least 33 peptides of which two have been shown to be immunodominant, i.e., to elicit activation and proliferation of autoimmune T cells. One of these two remnant epitopes contains a glycan which is important for its immunoreactivity. In addition to the role of gelatinase B as a regulator in adaptive immune processes, we have also demonstrated that it destroys interferon-beta, a typical innate immunity effector molecule and therapeutic cytokine in multiple sclerosis. Furthermore, glycosylated interferon-beta, expressed in Chinese hamster ovary cells, was more resistant to this proteolysis than recombinant interferon-beta from bacteria. These data not only prove that glycosylation of proteins is mechanistically important in the pathogenesis of autoimmune diseases, but also show that targeting of glycosylated proteinases or the use of glycosylated cytokines seems also critical for the treatment of autoimmune diseases.
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PMID:Remnant epitopes, autoimmunity and glycosylation. 1643 62