Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2

Nature. 2000 Mar 16;404(6775):298-302. doi: 10.1038/35005118.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Biological Transport
  • COS Cells
  • Caenorhabditis elegans
  • Calcium-Calmodulin-Dependent Protein Kinases*
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / embryology
  • Cerebral Cortex / physiology
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression Regulation*
  • Genes, Reporter
  • Guanylate Kinases
  • Helminth Proteins / metabolism
  • Hippocampus / cytology
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Nerve Tissue Proteins
  • Neurons / metabolism
  • Nucleoside-Phosphate Kinase / metabolism*
  • Protein Binding
  • Rats
  • Regulatory Sequences, Nucleic Acid
  • Serine Endopeptidases
  • T-Box Domain Proteins
  • Transcription Factors / physiology*
  • Transcription, Genetic

Substances

  • Cell Adhesion Molecules, Neuronal
  • DNA-Binding Proteins
  • Extracellular Matrix Proteins
  • Helminth Proteins
  • Lin-2 protein, C elegans
  • Membrane Proteins
  • Nerve Tissue Proteins
  • T-Box Domain Proteins
  • Tbr1 protein, mouse
  • Transcription Factors
  • DNA
  • CASK kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Nucleoside-Phosphate Kinase
  • Guanylate Kinases
  • Serine Endopeptidases
  • reelin protein

Associated data

  • GENBANK/AC002067