Nakamura Tsutomu, Hayashi Tomoatsu, Nasu-Nishimura Yukiko, Sakaue Fumika, Morishita Yasuyuki, Okabe Toshio, Ohwada Susumu, Matsuura Ken, Akiyama Tetsu
Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
Genes Dev. 2008 May 1;22(9):1244-56. doi: 10.1101/gad.1632308.
Cadherins mediate Ca2+-dependent cell-cell adhesion. Efficient export of cadherins from the endoplasmic reticulum (ER) is known to require complex formation with beta-catenin. However, the molecular mechanisms underlying this requirement remain elusive. Here we show that PX-RICS, a beta-catenin-interacting GTPase-activating protein (GAP) for Cdc42, mediates ER-to-Golgi transport of the N-cadherin/beta-catenin complex. Knockdown of PX-RICS expression induced the accumulation of the N-cadherin/beta-catenin complex in the ER and ER exit site, resulting in a decrease in cell-cell adhesion. PX-RICS was also required for ER-to-Golgi transport of the fibroblast growth factor-receptor 4 (FGFR4) associated with N-cadherin. PX-RICS-mediated ER-to-Golgi transport was dependent on its interaction with beta-catenin, phosphatidylinositol-4-phosphate (PI4P), Cdc42, and its novel binding partner gamma-aminobutyric acid type A receptor-associated protein (GABARAP). These results suggest that PX-RICS ensures the efficient entry of the N-cadherin/beta-catenin complex into the secretory pathway, and thereby regulates the amount of N-cadherin available for cell adhesion and FGFR4-mediated signaling.
钙黏蛋白介导钙离子依赖的细胞间黏附。已知钙黏蛋白从内质网（ER）的有效输出需要与β-连环蛋白形成复合物。然而，这一需求背后的分子机制仍不清楚。在这里，我们表明，PX-RICS是一种与β-连环蛋白相互作用的Cdc42的GTP酶激活蛋白（GAP），介导N-钙黏蛋白/β-连环蛋白复合物从内质网到高尔基体的运输。敲低PX-RICS的表达会导致N-钙黏蛋白/β-连环蛋白复合物在内质网和内质网出口位点积累，从而导致细胞间黏附减少。与N-钙黏蛋白相关的成纤维细胞生长因子受体4（FGFR4）从内质网到高尔基体的运输也需要PX-RICS。PX-RICS介导的内质网到高尔基体的运输依赖于它与β-连环蛋白、磷脂酰肌醇-4-磷酸（PI4P）、Cdc42及其新的结合伴侣γ-氨基丁酸A型受体相关蛋白（GABARAP）的相互作用。这些结果表明，PX-RICS确保N-钙黏蛋白/β-连环蛋白复合物有效地进入分泌途径，从而调节可用于细胞黏附和FGFR4介导信号传导的N-钙黏蛋白的量。
