title: Metalloprotease-induced ectodomain shedding of neural cell adhesion molecule (NCAM).
abstract: Transmembrane forms of neural cell adhesion molecule (NCAM140, NCAM180(1)) are key regulators of neuronal development. The extracellular domain of NCAM can occur as a soluble protein in normal brain, and its levels are elevated in neuropsychiatric disorders, such as schizophrenia; however the mechanism of ectodomain release is obscure. Ectodomain shedding of NCAM140, releasing a fragment of 115 kD, was found to be induced in NCAM-transfected L-fibroblasts by the tyrosine phosphatase inhibitor pervanadate, but not phorbol esters. Pervanadate-induced shedding was mediated by a disintegrin metalloprotease (ADAM), regulated by ERK1/2 MAP kinase. In primary cortical neurons, NCAM was shed at high levels, and the metalloprotease inhibitor GM6001 significantly increased NCAM-dependent neurite branching and outgrowth. Moreover, NCAM-dependent neurite outgrowth and branching were inhibited in neurons isolated from a transgenic mouse model of NCAM shedding. These results suggest that regulated metalloprotease-induced ectodomain shedding of NCAM down-regulates neurite branching and neurite outgrowth. Thus, increased levels of soluble NCAM in schizophrenic brain have the potential to impair neuronal connectivity.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: C Leann
authors.initials: CL
authors.lastname: Hinkle
authors.forename: Simone
authors.initials: S
authors.lastname: Diestel
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lieberman
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Maness
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
chemical_list: D015703:Antigens, CD; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D019006:Neural Cell Adhesion Molecules; D048049:Extracellular Signal-Regulated MAP Kinases; D017027:Protein Tyrosine Phosphatases; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; C489402:Adam8 protein, mouse; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse