title: Retinoic acid-induced upregulation of the metalloendopeptidase nardilysin is accelerated by co-expression of the brain-specific protein p42(IP4) (centaurin α 1; ADAP1) in neuroblastoma cells.
abstract: The mainly neuronally expressed protein p42(IP4) (centaurin α1; ADAP1), which interacts with the metalloendopeptidase nardilysin (NRD) was found to be localized in neuritic plaques in Alzheimer disease (AD) brains. NRD was shown to enhance the cleavage of the amyloid precursor protein (APP) by α-secretases, thereby increasing the release of neuroprotective sAPPα. We here investigated in vitro the biochemical interaction of p42(IP4) and NRD and studied the physiological interaction in SH-SY5Y cells. NRD is a member of the M16 family of metalloendopeptidases. Some members of this M16 family act bi-functionally, as protease and as non-enzymatic scaffold protein. Here, we show that p42(IP4) enhances the enzymatic activity of NRD 3-4 times. However, p42(IP4) is not a substrate for NRD. Furthermore, we report that differentiation of SH-SY5Y cells by stimulation with 10μM retinoic acid (RA) results in upregulation of NRD protein levels, with a 6-fold rise after 15 days. NRD is expressed in the neurites of RA-stimulated SH-SY5Y cells, and localized in vesicular structures. Since p42(IP4) is not expressed in untreated SH-SY5Y cells, we could use this cell system as a model to find out, whether there is a functional interaction. Interestingly, SH-SY5Y cells, which we stably transfected with GFP-tagged-p42(IP4) showed an enhanced NRD protein expression already at an earlier time point after RA stimulation.
authors.affiliation: Institut für Neurobiochemie, Medizinische Fakultät der Otto-von-Guericke-Universität Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Borrmann
authors.forename: Rolf
authors.initials: R
authors.lastname: Stricker
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D049408:Luminescent Agents; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: C100956:ADAP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D049408:Luminescent Agents; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins; D014212:Tretinoin; D008666:Metalloendopeptidases; C087976:nardilysin