Hsueh Y P, Yang F C, Kharazia V, Naisbitt S, Cohen A R, Weinberg R J, Sheng M
Howard Hughes Medical Institute and Department of Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
J Cell Biol. 1998 Jul 13;142(1):139-51. doi: 10.1083/jcb.142.1.139.
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.
CASK是秀丽隐杆线虫外阴分化所需基因（LIN-2）的大鼠同源物，在哺乳动物大脑中表达，但其在神经元中的功能尚不清楚。CASK在神经元中呈点状的体树突状分布模式。通过免疫金电子显微镜观察，CASK蛋白集中在突触中，但也存在于非突触膜和细胞内区室。这种免疫定位与生化研究一致，生化研究表明CASK存在于可溶性和突触体膜组分中，并且在大鼠脑的突触后致密组分中富集。通过酵母双杂交筛选，确定了CASK的PDZ结构域与syndecan-2（一种细胞表面硫酸乙酰肝素蛋白聚糖（HSPG））的COOH末端尾巴之间存在特异性相互作用。通过从异源细胞中共免疫沉淀证实了这种相互作用。在大脑中，syndecan-2特异性定位于突触连接处，在那里它与CASK显示出重叠分布，这与这些蛋白在突触中的相互作用一致。细胞表面HSPG可以与细胞外基质蛋白结合，并且是各种肝素结合多肽生长/分化因子发挥作用所必需的。CASK和syndecan的突触定位表明这些蛋白在神经元突触的黏附和信号传导中具有潜在作用。
