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Here, we report that the p75 neurotrophin receptor (p75NTR), a TNF receptor superfamily member up-regulated after tissue injury, blocks fibrinolysis by down-regulating the serine protease, tissue plasminogen activator (tPA), and up-regulating plasminogen activator inhibitor-1 (PAI-1). We have discovered a new mechanism in which phosphodiesterase PDE4A4\/5 interacts with p75NTR to enhance cAMP degradation. The p75NTR-dependent down-regulation of cAMP results in a decrease in extracellular proteolytic activity. This mechanism is supported in vivo in p75NTR-deficient mice, which show increased proteolysis after sciatic nerve injury and lung fibrosis. Our results reveal a novel pathogenic mechanism by which p75NTR regulates degradation of cAMP and perpetuates scar formation after injury.<\/jats:p>","DOI":"10.1083\/jcb.200701040","type":"journal-article","created":{"date-parts":[[2007,6,18]],"date-time":"2007-06-18T18:22:31Z","timestamp":1182190951000},"page":"1119-1132","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":116,"title":["p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4\/cAMP\/PKA pathway"],"prefix":"10.1083","volume":"177","author":[{"given":"Benjamin D.","family":"Sachs","sequence":"first","affiliation":[{"name":"1Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George S.","family":"Baillie","sequence":"additional","affiliation":[{"name":"2Molecular Pharmacology Group, Biochemistry & Molecular Biology, 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