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© The Rockefeller University Press, 0021-9525/1998//139 $5.00
The Journal of Cell Biology, Volume 142, Number 1, , 1998 139-151

Direct Interaction of CASK/LIN-2 and Syndecan Heparan Sulfate Proteoglycan and Their Overlapping Distribution in Neuronal Synapses

Yi-Ping Hsueh^*, Fu-Chia Yang^*, Viktor Kharazia, Scott Naisbitt^*, Alexandra R. Cohen, Richard J. Weinberg, and Morgan Sheng^*

^* Howard Hughes Medical Institute and Department of Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Department of Cell Biology and Anatomy, University of North Carolina, Chapel Hill, North Carolina 27599; Department of Cell Biology and Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06520

CASK, the rat homolog of a gene (LIN-2) required for vulval differentiation in Caenorhabditis elegans, is expressed in mammalian brain, but its function in neurons is unknown. CASK is distributed in a punctate somatodendritic pattern in neurons. By immunogold EM, CASK protein is concentrated in synapses, but is also present at nonsynaptic membranes and in intracellular compartments. This immunolocalization is consistent with biochemical studies showing the presence of CASK in soluble and synaptosomal membrane fractions and its enrichment in postsynaptic density fractions of rat brain. By yeast two-hybrid screening, a specific interaction was identified between the PDZ domain of CASK and the COOH terminal tail of syndecan-2, a cell surface heparan sulfate proteoglycan (HSPG). The interaction was confirmed by coimmunoprecipitation from heterologous cells. In brain, syndecan-2 localizes specifically at synaptic junctions where it shows overlapping distribution with CASK, consistent with an interaction between these proteins in synapses. Cell surface HSPGs can bind to extracellular matrix proteins, and are required for the action of various heparin-binding polypeptide growth/differentiation factors. The synaptic localization of CASK and syndecan suggests a potential role for these proteins in adhesion and signaling at neuronal synapses.

Key Words: CASK • LIN-2 • syndecan • heparan sulfate proteoglycan • PDZ domain

Abbreviations used in this paper: aa, amino acid; ECM, extracellular matrix; EGFR, EGF receptor; HCASK, rabbit anti-human CASK; HSPG, heparan sulfate proteoglycan; Kv1.4-EFYA, Kv1.4-syndecan-2 chimeric protein; MAGUK, membrane associated guanylate kinase; MB, maleate buffer; PB, phosphate buffer; PSD, postsynaptic density; SYN-2C, syndecan-2 antibody.

Address all correspondence to Morgan Sheng, Howard Hughes Medical Institute, Massachusetts General Hospital (Wel 423), 50 Blossom Street, Boston, MA 02114. Tel.: 617-724-2800; FAX: 617-724-2805; E-mail: sheng @http://helix.mgh.harvard.edu

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