DIRECT INTERACTION OF CASK LIN-2 AND SYNDECAN HEPARAN-SULFATE PROTEOGLYCAN AND THEIR OVERLAPPING DISTRIBUTION IN NEURONAL SYNAPSES/

CASK, the rat homolog of a gene (LIN-2) required for vulval differenti ation 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 consist ent with biochemical studies showing the presence of CASK in soluble a nd synaptosomal membrane fractions and its enrichment in postsynaptic density fractions of rat brain. By yeast two-hybrid screening, a speci fic interaction was identified between the PDZ domain of CASK and the COOH terminal tail of syndecan-2, a cell surface heparan sulfate prote oglycan (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 CAS K, 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 syndeca n suggests a potential role for these proteins in adhesion and signali ng at neuronal synapses.