p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway

Sachs, B.D. et al. (2007) p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. Journal of Cell Biology, 177(6), pp. 1119-1132. (doi: 10.1083%2Fjcb.200701040)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Houslay, Professor Miles and Baillie, Professor George and Lynch, Dr Martin
• Authors: Sachs, B.D., Baillie, G.S., McCall, J.R., Passino, M.A., Schachtrup, C., Wallace, D.A., Dunlop, A.J., MacKenzie, K.F., Klussmann, E., Lynch, M.J., Sikorski, S.L., Nuriel, T., Tsigelny, I., Zhang, J., Houslay, M.D., Chao, M.V., and Akassoglou, K.
• Subjects: Q Science > QH Natural history > QH301 Biology
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Journal of Cell Biology
• ISSN: 1540-8140