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

Nature volume 404, pages 298–302 (2000)Cite this article

A Corrigendum to this article was published on 09 May 2002

Abstract

Membrane-associated guanylate kinases (MAGUKs) contain multiple protein-binding domains that allow them to assemble specific multiprotein complexes in particular regions of the cell1,2. 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 domains3,4,5. In adult rat brain, CASK is concentrated at neuronal synapses and binds to the cell-surface proteins neurexin and syndecan6,7,8 and the cytoplasmic proteins Mint/LIN-10 and Veli/LIN-7 (refs 4, 9, 10). Here we report that, through its guanylate kinase domain, CASK interacts with Tbr-1, a T-box transcription factor that is involved in forebrain development11,12. 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.

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Figure 1: Specific interaction of CASK and Tbr-1.
Figure 2: Tbr-1-dependent nuclear translocation of CASK.
Figure 3: Tbr-1–CASK complex binds to T-element DNA.
Figure 4: CASK is found with Tbr-1 in nuclei of neurons in embryonic rat cerebral cortex.
Figure 5: CASK stimulates transcriptional activity of Tbr-1 in COS-7 cells.
Figure 6: Tbr-1/CASK complex activates gene expression in cultured neurons.

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Acknowledgements

We thank J. Trimmer and L. Buchwalder for CASK monoclonal antibodies; C. Konradi for luciferase reporter plasmid ΔERSV90-luc; A. Kispert for Brachyury (T) cDNA; M. Greenberg and J. Kornhauser for GAL-4 reporter vectors; L.-H. Tsai and Y. Kwon for advice on embryonic brain immunohistochemistry. M.S. is Assistant Investigator of the Howard Hughes Medical Institute. This work was supported by the NIH (M.S.) and a National Neurofibromatosis Foundation Young Investigator Award (Y.-P.H.).

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  1. Ting-Fang Wang

    Present address: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, 02138, USA

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  1. Howard Hughes Medical Institute and Department of Neurobiology Massachusetts General Hospital and Harvard Medical School, Boston , 02114, Massachusetts, USA

    Yi-Ping Hsueh, Ting-Fang Wang & Morgan Sheng

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Correspondence to Morgan Sheng.

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Hsueh, YP., Wang, TF., Yang, FC. et al. Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature 404, 298–302 (2000). https://doi.org/10.1038/35005118

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