title: Neurotrophins regulate ApoER2 proteolysis through activation of the Trk signaling pathway.
abstract: BACKGROUND
  ApoER2 and the neurotrophin receptors Trk and p75(NTR) are expressed in the CNS and regulate key functional aspects of neurons, including development, survival, and neuronal function. It is known that both ApoER2 and p75(NTR) are processed by metalloproteinases, followed by regulated intramembrane proteolysis. TrkA activation by nerve growth factor (NGF) increases the proteolytic processing of p75(NTR) mediated by ADAM17. Reelin induces the sheeding of ApoER2 ectodomain depending on metalloproteinase activity. However, it is not known if there is a common regulation mechanism for processing these receptors.
  
  
  RESULTS
  We found that TrkA activation by NGF in PC12 cells induced ApoER2 processing, which was dependent on TrkA activation and metalloproteinases. NGF-induced ApoER2 proteolysis was independent of mitogen activated protein kinase activity and of phosphatidylinositol-3 kinase activity. In contrast, the basal proteolysis of ApoER2 increased when both kinases were pharmacologically inhibited. The ApoER2 ligand reelin regulated the proteolytic processing of its own receptor but not of p75(NTR). Finally, in primary cortical neurons, which express both ApoER2 and TrkB, we found that the proteolysis of ApoER2 was also regulated by brain-derived growth factor (BDNF).
  
  
  CONCLUSIONS
  Our results highlight a novel relationship between neurotrophins and the reelin-ApoER2 system, suggesting that these two pathways might be linked to regulate brain development, neuronal survival, and some pathological conditions.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Larios
authors.forename: Ignacio
authors.initials: I
authors.lastname: Jausoro
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Benitez
authors.forename: Francisca C
authors.initials: FC
authors.lastname: Bronfman
authors.affiliation: Departamento de Biología Celular y Molecular, Laboratorio de Tráfico Intracelular y Señalización, Facultad de Ciencias Biológicas, Pontificia Universidad Católica, Alameda 340, Santiago 8320000, Chile. mmarzolo@bio.puc.cl.
authors.forename: Maria-Paz
authors.initials: MP
authors.lastname: Marzolo
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D045726:Metalloproteases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism*; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D026502:LDL-Receptor Related Proteins; D045726:Metalloproteases; D020932:Nerve Growth Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020917:Receptor, trkA; D020813:Receptor, trkB; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D000091042:Reelin Protein; D012697:Serine Endopeptidases; C000717129:Reln protein, rat; C098773:low density lipoprotein receptor-related protein 8; C068313:Ngfr protein, rat