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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Craven, S. E. & Bredt, D. S. PDZ proteins organize synaptic signaling pathways. Cell 93, 495– 498. (1998).
Anderson, J. M. Cell signalling: MAGUK magic. Curr. Biol. 6, 382–384 (1996).
Kim, S. K. Polarized signaling: basolateral receptor localization in epithelial cells by PDZ-containing proteins. Curr. Opin. Cell Biol. 9, 853–859 (1997).
Kaech, S. M., Whitfield, C. W. & Kim, S. K. The LIN-2/LIN-7/LIN-10 complex mediates basolateral membrane localization of the C. elegans EGF receptor LET-23 in vulval epithelial cells. Cell 94, 761– 771 (1998).
Bredt, D. S. Sorting out genes that regulate epithelial and neuronal polarity. Cell 94, 691–694 ( 1998).
Hata, Y., Butz, S. & Südhof, T. C. CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J. Neurosci. 16, 2488– 2494 (1996).
Hsueh, Y. -P. et al. Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses. J. Cell Biol. 142, 139– 151 (1998).
Cohen, A. R. et al. Human Cask/Lin-2 binds syndecan-2 and protein 4. 1 and localizes to the basolateral membrane of epithelial cells. J. Cell Biol. 142, 129–138 ( 1998).
Borg, J. P. et al. Identification of an evolutionarily conserved heterotrimeric protein complex involved in protein targeting. J. Biol. Chem. 273, 31633–31636 (1998).
Butz, S., Okamoto, M. & Südhof, T. C. A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Cell 94, 773–782 ( 1998).
Bulfone, A. et al. T-brain-1: a homolog of Brachyury whose expression defines molecularly distinct domains within the cerebral cortex. Neuron 15, 63–78 ( 1995).
Hevner, R. F., Shi, L., LeWinter, R. & Rubenstein, J. L. R. Cortical phenotype of Tbr-1 mutant mice: laminar inversion and decreased expression of Reelin. Soc. Neurosci. Abstr. 25, 502 (1999).
Hsueh, Y. P. & Sheng, M. Regulated expression and subcellular localization of syndecan heparan sulfate proteoglycans and the syndecan-binding protein CASK/LIN-2 during rat brain development. J. Neurosci. 19, 7415–7425 (1999).
Kispert, A., Koschorz, B. & Herrmann, B. G. The T protein encoded by Brachyury is a tissue-specific transcription factor. EMBO J. 14, 4763– 4772 (1995).
Miller, J. R. & Moon, R. T. Signal transduction through beta-catenin and specification of cell fate during embryogenesis. Genes Dev. 10, 2527–2539 ( 1996).
Peifer, M. β-catenin as oncogene: the smoking gun. Science 275, 1752–1753 (1997).
Gottardi, C. J., Arpin M., Fanning, A. S. & Louvard, D. The junction-associated protein, zonula occludens-1, localizes to the nucleus before the maturation and during the remodeling of cell-cell contacts. Proc. Natl Acad. Sci. USA 93, 10779–10784 (1996).
Hsueh, Y. -P. & Sheng, M. Requirement of N-terminal cysteines of PSD-95 for PSD-95 multimerization and ternary complex formation, but not for binding to potassium channel Kv1. 4. J. Biol. Chem. 174, 532–536 (1999).
Gorski, K., Carneiro, M. & Schibler, U. Tissue-specific in vitro transcription from the mouse albumin promoter. Cell 47, 767– 776 (1986).
Hsueh, Y.-P. & Lai, M.-Z. Overexpression of activation transcriptional factor 1 in lymphomas and in activated lymphocytes. J. Immunol. 154, 5675–5683 ( 1995).
Niethammer, M. & Sheng, M. Identification of ion channel-associated proteins using the yeast two-hybrid system. Methods Enzymol. 293, 104–122 (1998).
Kim, E. et al. GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules. J. Cell Biol. 136, 669– 678 (1997).
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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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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DOI: https://doi.org/10.1038/35005118
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