Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Mol Biol Cell. 2009 Nov;20(21):4489-99. doi: 10.1091/mbc.e09-04-0280. Epub 2009 Sep 2.
CASK is the mammalian ortholog of LIN2, a component of the LIN2/7/10 protein complex that targets epidermal growth factor receptor (EGFR) to basolateral membranes in Caenorhabditis elegans. A member of the MAGUK family of scaffolding proteins, CASK resides at basolateral membranes in polarized epithelia. Its interaction with LIN7 is evolutionarily conserved. In addition, CASK forms a complex with another MAGUK, the DLG1 tumor suppressor. Although complete knockout of CASK is lethal, the gene is X-linked, enabling us to generate heterozygous female adults that are mosaic for its expression. We also generated intestine-specific CASK knockout mice. Immunofluorescence analysis revealed that in intestine, CASK is not required for epithelial polarity or differentiation but is necessary for the basolateral localization of DLG1 and LIN7C. However, the subcellular distributions of DLG1 and LIN7C are independent of CASK in the stomach. Moreover, CASK and LIN7C show normal localization in dlg1(-/-) intestine. Despite the disappearance of basolateral LIN7C in CASK-deficient intestinal crypts, this epithelium retains normal localization of LIN7A/B, EGFR and ErbB-2. Finally, crypt-to-villus migration rates are unchanged in CASK-deficient intestinal epithelium. Thus, CASK expression and the appropriate localization of DLG1 are not essential for either epithelial polarity or intestinal homeostasis in vivo.
CASK 是哺乳动物 LIN2 的同源物，是 LIN2/7/10 蛋白复合物的一个组成部分，该复合物将表皮生长因子受体 (EGFR) 靶向到秀丽隐杆线虫的基底外侧膜。CASK 是支架蛋白 MAGUK 家族的成员，位于极化上皮的基底外侧膜。它与 LIN7 的相互作用在进化上是保守的。此外，CASK 与另一个 MAGUK，即 DLG1 肿瘤抑制因子形成复合物。虽然 CASK 的完全敲除是致命的，但该基因是 X 连锁的，使我们能够产生其表达呈镶嵌性的杂合雌性成年个体。我们还生成了肠道特异性 CASK 敲除小鼠。免疫荧光分析显示，在肠道中，CASK 对于上皮极性或分化不是必需的，但对于 DLG1 和 LIN7C 的基底外侧定位是必需的。然而，在胃中，DLG1 和 LIN7C 的亚细胞分布与 CASK 无关。此外，在 dlg1(-/-) 肠道中 CASK 和 LIN7C 显示出正常的定位。尽管 CASK 缺陷的肠隐窝中基底外侧 LIN7C 消失，但这种上皮保留了 LIN7A/B、EGFR 和 ErbB-2 的正常定位。最后，CASK 缺陷的肠上皮中隐窝到绒毛的迁移率没有变化。因此，CASK 表达和 DLG1 的适当定位对于体内上皮极性或肠道稳态不是必需的。
