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.
(c) 2006 Wiley Periodicals, Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ADAM Proteins / antagonists & inhibitors
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ADAM Proteins / chemistry
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ADAM Proteins / metabolism*
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ADAM10 Protein
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Amyloid Precursor Protein Secretases / metabolism
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Animals
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Antigens, CD / metabolism
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Brain / cytology
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Brain / embryology*
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Brain / metabolism*
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Cell Differentiation / physiology*
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Cell Line, Tumor
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Cerebral Cortex / cytology
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Cerebral Cortex / embryology
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Cerebral Cortex / metabolism
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Disease Models, Animal
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Down-Regulation / physiology
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neural Cell Adhesion Molecules / metabolism*
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Neurites / metabolism
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Neurites / ultrastructure
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Neurons / cytology
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Neurons / metabolism*
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Protein Structure, Tertiary / physiology
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Protein Tyrosine Phosphatases / antagonists & inhibitors
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Protein Tyrosine Phosphatases / metabolism
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Schizophrenia / genetics
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Schizophrenia / metabolism
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Schizophrenia / physiopathology
Substances
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Antigens, CD
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Enzyme Inhibitors
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Membrane Proteins
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Neural Cell Adhesion Molecules
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Extracellular Signal-Regulated MAP Kinases
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Protein Tyrosine Phosphatases
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Amyloid Precursor Protein Secretases
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ADAM Proteins
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Adam8 protein, mouse
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ADAM10 Protein
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Adam10 protein, mouse