Abstract
Membrane-associated guanylate kinases (MAGUKs) contain multiple protein-binding domains that allow them to assemble specific multiprotein complexes in particular regions of the cell. CASK/LIN-2, a MAGUK required for EGF receptor localization and signalling in Caenorhabditis elegans, contains a calmodulin-dependent protein kinase-like domain followed by PDZ, SH3 and guanylate kinase-like domains. In adult rat brain, CASK is concentrated at neuronal synapses and binds to the cell-surface proteins neurexin and syndecan and the cytoplasmic proteins Mint/LIN-10 and Veli/LIN-7. Here we report that, through its guanylate kinase domain, CASK interacts with Tbr-1, a T-box transcription factor that is involved in forebrain development. CASK enters the nucleus and binds to a specific DNA sequence (the T-element) in a complex with Tbr-1. CASK acts as a coactivator of Tbr-1 to induce transcription of T-element containing genes, including reelin, a gene that is essential for cerebrocortical development. Our findings show that a MAGUK which is usually associated with cell junctions has a transcription regulation function.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites
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Biological Transport
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COS Cells
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Caenorhabditis elegans
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Calcium-Calmodulin-Dependent Protein Kinases*
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Cell Adhesion Molecules, Neuronal / metabolism
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Cell Nucleus / metabolism*
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Cells, Cultured
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Cerebral Cortex / embryology
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Cerebral Cortex / physiology
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DNA / metabolism
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DNA-Binding Proteins / metabolism
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Extracellular Matrix Proteins / metabolism
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Gene Expression Regulation*
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Genes, Reporter
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Guanylate Kinases
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Helminth Proteins / metabolism
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Hippocampus / cytology
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Membrane Proteins / metabolism
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Mice
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Molecular Sequence Data
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Nerve Tissue Proteins
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Neurons / metabolism
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Nucleoside-Phosphate Kinase / metabolism*
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Protein Binding
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Rats
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Reelin Protein
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Regulatory Sequences, Nucleic Acid
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Serine Endopeptidases
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T-Box Domain Proteins
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Transcription Factors / physiology*
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Transcription, Genetic
Substances
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Cell Adhesion Molecules, Neuronal
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DNA-Binding Proteins
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Extracellular Matrix Proteins
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Helminth Proteins
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Lin-2 protein, C elegans
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Membrane Proteins
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Nerve Tissue Proteins
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Reelin Protein
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Reln protein, rat
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T-Box Domain Proteins
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Tbr1 protein, mouse
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Transcription Factors
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DNA
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CASK kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Nucleoside-Phosphate Kinase
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Guanylate Kinases
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Reln protein, mouse
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Serine Endopeptidases