Abstract
Receptor protein tyrosine phosphatase alpha (RPTPalpha) phosphatase activity is required for intracellular signaling cascades that are activated in motile cells and growing neurites. Little is known, however, about mechanisms that coordinate RPTPalpha activity with cell behavior. We show that clustering of neural cell adhesion molecule (NCAM) at the cell surface is coupled to an increase in serine phosphorylation and phosphatase activity of RPTPalpha. NCAM associates with T- and L-type voltage-dependent Ca(2+) channels, and NCAM clustering at the cell surface results in Ca(2+) influx via these channels and activation of NCAM-associated calmodulin-dependent protein kinase IIalpha (CaMKIIalpha). Clustering of NCAM promotes its redistribution to lipid rafts and the formation of a NCAM-RPTPalpha-CaMKIIalpha complex, resulting in serine phosphorylation of RPTPalpha by CaMKIIalpha. Overexpression of RPTPalpha with mutated Ser180 and Ser204 interferes with NCAM-induced neurite outgrowth, which indicates that neurite extension depends on NCAM-induced up-regulation of RPTPalpha activity. Thus, we reveal a novel function for a cell adhesion molecule in coordination of cell behavior with intracellular phosphatase activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium Channels / metabolism
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
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Cells, Cultured
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Enzyme Activation
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Membrane Microdomains / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Multiprotein Complexes / metabolism
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Neural Cell Adhesion Molecules / genetics
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Neural Cell Adhesion Molecules / metabolism*
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Neurites / metabolism*
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Neurons / cytology
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Neurons / metabolism
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Phosphorylation
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Protein Kinase C-delta / genetics
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Protein Kinase C-delta / metabolism
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Proto-Oncogene Proteins c-fyn / genetics
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Proto-Oncogene Proteins c-fyn / metabolism
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Receptor-Like Protein Tyrosine Phosphatases, Class 4 / genetics
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Receptor-Like Protein Tyrosine Phosphatases, Class 4 / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Serine / metabolism
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Signal Transduction / physiology
Substances
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Calcium Channels
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Multiprotein Complexes
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Neural Cell Adhesion Molecules
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Recombinant Fusion Proteins
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Serine
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Proto-Oncogene Proteins c-fyn
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Protein Kinase C-delta
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Receptor-Like Protein Tyrosine Phosphatases, Class 4