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)

In vitro findings suggest that alpha 2M is an important regulator of PDGF-stimulated fibroblast proliferation and chemotaxis. Native alpha 2M binds to PDGF and prevents PDGF from interacting with its receptor, but serves as an extracellular reservoir for the growth factor, which can be released over time in a controlled fashion to interact with the PDGF-alpha or -beta receptor. Methylamine-activated alpha 2M synergistically enhances PDGF-induced cell growth, whereas plasmin-activated alpha 2M inhibits PDGF-stimulated fibroblast proliferation. The reason for the difference in the effect of these two receptor-recognized alpha 2Ms is unknown. PDGF secreted by rat alveolar macrophages is bound to homologues of human alpha 2M and it has been suggested that PDGF action in the lung is tightly controlled during normal tissue remodeling. It is important to consider another regulator of PDGF termed SPARC (secreted protein, acidic and rich in cysteine), which inhibits the binding of PDGF-BB and -AB to cell-surface PDGF-beta receptors. SPARC could modulate PDGF activity during inflammation and tissue repair by limiting the availability of dimers containing the PDGF B chain. Future studies should address the relative importance of SPARC and alpha 2M in regulating PDGF-induced chemotaxis and proliferation. During inflammation or during the progression of fibroproliferative lung disease, the regulation of PDGF might be lost. For example, oxidative bursts from inflammatory cells (neutrophils and eosinophils) functionally inactivate alpha 2M. Thus, inhaled environmental insults (particles and oxidants) could perturb the normal growth regulatory signaling system between cells via the network that includes cytokines, alpha 2M, and proteinases.
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PMID:Regulation of platelet-derived growth factor (PDGF) and alveolar macrophage-derived PDGF by alpha 2-macroglobulin. 752 5

SPARC is a secreted glycoprotein that has been shown to disrupt focal adhesions and to regulate the proliferation of endothelial cells in vitro. Moreover, peptides resulting from the proteolysis of SPARC exhibit angiogenic activity. Here we describe the temporal synthesis, turnover, and angiogenic potential of SPARC in the chicken chorioallantoic membrane. Confocal immunofluorescence microscopy revealed specific expression of SPARC protein in endothelial cells, and significantly higher levels of SPARC were observed in smaller newly formed blood vessels in comparison to larger, developmentally older vessels. SPARC mRNA was detected at the earliest stages of chorioallantoic membrane morphogenesis and reached maximal levels at day 13 of embryonic development. Interestingly, steady-state levels of SPARC mRNA did not correlate directly with protein accumulation; moreover, the protein appeared to undergo limited degradation during days 10-15. Incubation of [125I]-SPARC with chorioallantoic membranes of different developmental ages confirmed that extracellular proteolysis occurred during days 9-15, but not at later stages (e.g., days 17-21). Comparison of peptides produced by incubation with chorioallantoic membranes with those generated by plasmin showed an identical pattern of proteolysis. Plasmin activity was present throughout development, and in situ zymography identified sites of plasminogen activator activity that corresponded to areas exhibiting high levels of SPARC expression. Synthetic peptides from a plasmin-sensitive region of SPARC, between amino acids 113-130, stimulated angiogenesis in the chorioallantoic membrane in a dose-dependent manner; in contrast, intact SPARC was inactive in similar assays. We have shown that SPARC is expressed in endothelial cells of newly formed blood vessels in a manner that is both temporally and spatially restricted. Between days 9 and 15 of chorioallantoic membrane development, the protein undergoes proteolytic cleavage that is mediated, in part, by plasmin. SPARC peptides released specifically by plasmin induce angiogenesis in vivo. We therefore propose that SPARC acts as an intrinsic regulator of angiogenesis in vivo.
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PMID:Expression of SPARC during development of the chicken chorioallantoic membrane: evidence for regulated proteolysis in vivo. 761 67

By employing the cationic colloidal silica membrane density perturbation technique, we examined growth factor receptor and extracellular matrix (ECM) changes at the sinusoidal surface during rat liver regeneration 72 hours after 70% partial hepatectomy (PHx). At this time after PHx, hepatocyte division has mostly subsided, while sinusoidal endothelial cell (SEC) proliferation is initiating, resulting in avascular hepatocyte islands. Because of the discontinuous nature of the surface of liver SEC, ECM proteins underlying the SEC, as well as SEC luminal membrane proteins, are available to absorption to the charged silica beads when the liver is perfused with the colloid. Subsequent liver homogenization and density centrifugation yield two separate fractions, enriched in SECs as well as hepatocyte basolateral membrane-specific proteins up to 50-fold over whole liver lysates. This technique facilitates examination of changes in protein composition that influence or occur as a result of SEC mitogenesis and migration during regeneration of the liver. When ECM and receptor proteins from SEC-enriched fractions were examined by Western immunoblotting, urokinase plasminogen activator receptor, fibronectin, and plasmin increased at the SEC surface 72 hours after PHx. Epidermal growth factor receptor, plasminogen, SPARC (secreted protein, acidic and rich in cysteine, also called osteonectin or BM40), and collagen IV decreased, and fibrinogen subunits and c-Met expression remained constant 72 hours after PHx when compared to control liver. These results display the usefulness of the cationic colloidal silica membrane isolation protocol. They also show considerable modulation of surface components that may regulate angiogenic processes at the end stage of liver regeneration during the reformation of sinusoids.
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PMID:Cationic colloidal silica membrane perturbation as a means of examining changes at the sinusoidal surface during liver regeneration. 1055 Mar 5

Secreted protein acidic and rich in cysteine (SPARC/osteonectin/BM-40) is a matricellular protein that functions in wound healing. Fibrinogen is a plasma protein involved in many aspects of wound healing, such as inflammation, fibrosis and thrombosis. In this study, the binding of SPARC to both native and plasmin-cleaved fibrinogen under physiological conditions was examined by the use of a surface plasmon resonance (SPR) biosensor. We show that SPARC binds to plasmin-cleaved fibrinogen, but not to native fibrinogen. SPARC binds to both fibrinogen fragments D and E fg D and fg E with similar dissociation constants (8.67 x 10(-8) M for Fg D and 1.61 x 10(-7) M for Fg E). Results from endothelial cell proliferation assays show that the binding of SPARC to Fg E suppressed the inhibition of proliferation by SPARC, whereas the binding of SPARC to Fg D did not influence the activity of SPARC on the cell cycle. The interaction of SPARC with fibrinogen fragments D and E, which are produced as a result of proteolytic activation of fibrinolysis, reveals potential storage sites in provisional extracellular matrix for SPARC during the wound healing process and indicates a regulatory role of SPARC in fibrinolysis and angiogenesis.
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PMID:Secreted protein acidic and rich in cysteine (SPARC/osteonectin/BM-40) binds to fibrinogen fragments D and E, but not to native fibrinogen. 1626 53