Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2.
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.
Hsueh
Y P
YP
Howard Hughes Medical Institute and Department of Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Wang
T F
TF
Yang
F C
FC
Sheng
M
M
D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D019556:COS Cells; D017173:Caenorhabditis elegans; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology / Q000502:physiology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D051528:Guanylate Kinases; D015801:Helminth Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D000091042:Reelin Protein; D012045:Regulatory Sequences, Nucleic Acid; D012697:Serine Endopeptidases; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
D015816:Cell Adhesion Molecules, Neuronal; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D015801:Helminth Proteins; C097978:Lin-2 protein, C elegans; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; D020825:T-Box Domain Proteins; C492271:Tbr1 protein, mouse; D014157:Transcription Factors; D004247:DNA; C106868:CASK kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases