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)

Chronic inflammatory diseases are associated with connective tissue turnover that involves a series of proteases, which include the plasminogen activation system and the family of matrix metalloproteinases (MMPs). Urokinase-type plasminogen activator (uPA) and plasmin, in addition to their role in fibrinolysis and activation of pro-MMPs, have been shown to transduce intracellular signals through specific receptors. The potential for uPA and plasmin to also contribute to connective tissue turnover by directly regulating MMP production was examined in human monocytes. Both catalytically active high m.w. uPA, which binds to the uPAR, and low m.w. uPA, which does not, significantly enhanced MMP-1 synthesis by activated human monocytes. In contrast, the N-terminal fragment of uPA, which binds to uPAR, but lacks the catalytic site, failed to induce MMP-1 production, indicating that uPA-stimulated MMP-1 synthesis was plasmin dependent. Endogenous plasmin generated by the action of uPA or exogenous plasmin increased MMP-1 synthesis by signaling through annexin A2, as demonstrated by inhibition of MMP-1 production with Abs against annexin A2 and S100A10, a dimeric protein associated with annexin A2. Interaction of plasmin with annexin A2 resulted in the stimulation of ERK1/2 and p38 MAPK, cyclooxygenase-2, and PGE(2), leading to increased MMP-1 production. Furthermore, binding of inactive plasmin to annexin A2 inhibited plasmin induction of MMP-1, suggesting that inactive plasmin may be useful in suppressing inflammation.
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PMID:Urokinase-type plasminogen activator stimulation of monocyte matrix metalloproteinase-1 production is mediated by plasmin-dependent signaling through annexin A2 and inhibited by inactive plasmin. 1770 46

Collagen deposition by fibroblasts contributes to scarring in fibrotic diseases. Activation of protein kinase A (PKA) by cAMP represents a pivotal brake on fibroblast activation, and the lipid mediator prostaglandin E(2) (PGE(2)) exerts its well known anti-fibrotic actions through cAMP signaling. However, fibrotic fibroblasts from the lungs of patients with idiopathic pulmonary fibrosis, or of mice with bleomycin-induced fibrosis, are resistant to the normal collagen-inhibiting action of PGE(2). In this study, we demonstrate that plasminogen activation to plasmin restores PGE(2) sensitivity in fibrotic lung fibroblasts from human and mouse. This involves amplified PKA signaling resulting from the promotion of new interactions between AKAP9 and PKA regulatory subunit II in the perinuclear region as well as from the inhibition of protein phosphatase 2A. This is the first report to show that an extracellular mediator can dramatically reorganize and amplify the intracellular PKA-A-kinase anchoring protein signaling network and suggests a new strategy to control collagen deposition by fibrotic fibroblasts.
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PMID:Plasmin overcomes resistance to prostaglandin E2 in fibrotic lung fibroblasts by reorganizing protein kinase A signaling. 2179 91