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¹ Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093
² Molecular Pharmacology Group, Biochemistry & Molecular Biology, University of Glasgow, Glasgow G12 8QQ, Scotland, UK
³ Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch,13125 Berlin, Germany
⁴ Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology, and Neuroscience, New York University School of Medicine, New York, NY 10016

Correspondence to Katerina Akassoglou: akass{at}ucsd.edu

Clearance of fibrin through proteolytic degradation is a critical step of matrix remodeling that contributes to tissue repair in a variety of pathological conditions, such as stroke, atherosclerosis, and pulmonary disease. However, the molecular mechanisms that regulate fibrin deposition are not known. Here, we report that the p75 neurotrophin receptor (p75^NTR), 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 p75^NTR to enhance cAMP degradation. The p75^NTR-dependent down-regulation of cAMP results in a decrease in extracellular proteolytic activity. This mechanism is supported in vivo in p75^NTR-deficient mice, which show increased proteolysis after sciatic nerve injury and lung fibrosis. Our results reveal a novel pathogenic mechanism by which p75^NTR regulates degradation of cAMP and perpetuates scar formation after injury.

T. Nuriel's present address is Weill Medical School of Cornell University, 1300 York Avenue, New York, NY 10021.

J. Zhang's present address is Department of Pharmacology and Molecular Sciences and Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.

Abbreviations used in this paper: 3D, three-dimensional; BDNF, brain-derived neurotrophic factor; CGN, cerebellar granule neuron; FL, full length; FRET, fluorescence resonance energy transfer; ICD, intracellular domain; IP, immunoprecipitation; LPS, lipopolysaccharide; MS, multiple sclerosis; NGF, nerve growth factor, p75^NTR, p75 neurotrophin receptor; PA, plasminogen activator; PAI-1, plasminogen activator inhibitor-1; PDE, phosphodiesterase; PTX, pertussis toxin; SC, Schwann cell; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; wt, wild-type.

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