RGD Reference Report - p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. - Rat Genome Database

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

Authors: Sachs, BD  Baillie, GS  McCall, JR  Passino, MA  Schachtrup, C  Wallace, DA  Dunlop, AJ  MacKenzie, KF  Klussmann, E  Lynch, MJ  Sikorski, SL  Nuriel, T  Tsigelny, I  Zhang, J  Houslay, MD  Chao, MV  Akassoglou, K 
Citation: Sachs BD, etal., J Cell Biol. 2007 Jun 18;177(6):1119-32.
RGD ID: 5144067
Pubmed: PMID:17576803   (View Abstract at PubMed)
PMCID: PMC2064370   (View Article at PubMed Central)
DOI: DOI:10.1083/jcb.200701040   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pulmonary fibrosis  ISONgfr (Mus musculus)5144067; 5144067 RGD 
pulmonary fibrosis  IMP 5144067 RGD 
sciatic neuropathy  ISONgfr (Mus musculus)5144067; 5144067 RGD 
sciatic neuropathy  IMP 5144067 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ngfr  (nerve growth factor receptor)

Genes (Mus musculus)
Ngfr  (nerve growth factor receptor (TNFR superfamily, member 16))

Genes (Homo sapiens)
NGFR  (nerve growth factor receptor)


Additional Information