TY - JOUR
T1 - p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway
AU - Sachs, Benjamin D.
AU - Baillie, George S.
AU - McCall, Julianne R.
AU - Passino, Melissa A.
AU - Schachtrup, Christian
AU - Wallace, Derek A.
AU - Dunlop, Allan J.
AU - MacKenzie, Kirsty F.
AU - Klussmann, Enno
AU - Lynch, Martin J.
AU - Sikorski, Shoana L.
AU - Nuriel, Tal
AU - Tsigelny, Igor
AU - Zhang, Jin
AU - Houslay, Miles D.
AU - Chao, Moses V.
AU - Akassoglou, Katerina
PY - 2007/6/18
Y1 - 2007/6/18
N2 - 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 (p75NTR), a TNF receptor superfamily member up-regulated after tissue injury, blocks fibrinolysis by down-regulating the serine protease, tissue plasminogen activator (tPA), and upregulating 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-defi cient 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.
AB - 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 (p75NTR), a TNF receptor superfamily member up-regulated after tissue injury, blocks fibrinolysis by down-regulating the serine protease, tissue plasminogen activator (tPA), and upregulating 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-defi cient 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.
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U2 - 10.1083/jcb.200701040
DO - 10.1083/jcb.200701040
M3 - Article
C2 - 17576803
AN - SCOPUS:34250732324
SN - 0021-9525
VL - 177
SP - 1119
EP - 1132
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 6
ER -