title: Prolyl endopeptidase is involved in the degradation of neural cell adhesion molecules in vitro.
abstract: Membrane-associated glycoprotein neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) play an important role in brain plasticity by regulating cell-cell interactions. Here, we demonstrate that the cytosolic serine protease prolyl endopeptidase (PREP) is able to regulate NCAM and PSA-NCAM. Using a SH-SY5Y neuroblastoma cell line with stable overexpression of PREP, we found a remarkable loss of PSA-NCAM, reduced levels of NCAM180 and NCAM140 protein species, and a significant increase in the NCAM immunoreactive band migrating at an apparent molecular weight of 120 kDa in PREP-overexpressing cells. Moreover, increased levels of NCAM fragments were found in the concentrated medium derived from PREP-overexpressing cells. PREP overexpression selectively induced an activation of matrix metalloproteinase-9 (MMP-9), which could be involved in the observed degradation of NCAM, as MMP-9 neutralization reduced the levels of NCAM fragments in cell culture medium. We propose that increased PREP levels promote epidermal growth factor receptor (EGFR) signaling, which in turn activates MMP-9. In conclusion, our findings provide evidence for newly-discovered roles for PREP in mechanisms regulating cellular plasticity through NCAM and PSA-NCAM.
authors: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia Kulli.Jaako@ut.ee.
authors: Külli
authors: 0000-0003-4675-5188
authors: K
authors: Jaako
authors: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig 04103, Germany.
authors: Alexander
authors: A
authors: Waniek
authors: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia.
authors: Keiti
authors: K
authors: Parik
authors: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia.
authors: Linda
authors: 0000-0001-7085-3891
authors: L
authors: Klimaviciusa
authors: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia.
authors: Anu
authors: A
authors: Aonurm-Helm
authors: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia.
authors: Aveli
authors: A
authors: Noortoots
authors: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia.
authors: Kaili
authors: K
authors: Anier
authors: Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp B-2610, Belgium.
authors: Roos
authors: R
authors: Van Elzen
authors: Interdisciplinary Research Centre KU Leuven-Kortrijk, Kortrijk B-8500, Belgium.
authors: Melanie
authors: M
authors: Gérard
authors: Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp B-2610, Belgium.
authors: Anne-Marie
authors: AM
authors: Lambeir
authors: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig 04103, Germany.
authors: Steffen
authors: S
authors: Roßner
authors: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig 04103, Germany.
authors: Markus
authors: M
authors: Morawski
authors: Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia.
authors: Alexander
authors: A
authors: Zharkovsky
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003470:Culture Media; D066246:ErbB Receptors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000085822:Prolyl Oligopeptidases; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D012794:Sialic Acids / Q000378:metabolism; D012799:Sialyltransferases / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D003470:Culture Media; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012794:Sialic Acids; C103469:polysialyl neural cell adhesion molecule; D012799:Sialyltransferases; D066246:ErbB Receptors; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases; D020780:Matrix Metalloproteinase 9
keywords: Metalloproteinase-9; Neural cell adhesion molecule; Neuronal plasticity; Prolyl endopeptidase