Metalloprotease-induced ectodomain shedding of neural cell adhesion molecule (NCAM).
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.
Hinkle
C Leann
CL
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Diestel
Simone
S
Lieberman
Jeffrey
J
Maness
Patricia F
PF
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
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