PX-RICS mediates ER-to-Golgi transport of the N-cadherin/beta-catenin complex.
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.
Nakamura
Tsutomu
T
Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan. nakamura@iam.u-tokyo.ac.jp
Hayashi
Tomoatsu
T
Nasu-Nishimura
Yukiko
Y
Sakaue
Fumika
F
Morishita
Yasuyuki
Y
Okabe
Toshio
T
Ohwada
Susumu
S
Matsuura
Ken
K
Akiyama
Tetsu
T
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015820:Cadherins / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
C470196:ARHGAP32 protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D015820:Cadherins; C116741:GABARAP protein, human; C430503:GABARAPL1 protein, human; C477752:GC-GAP protein, mouse; D020690:GTPase-Activating Proteins; D008869:Microtubule-Associated Proteins; D018129:Phosphatidylinositol Phosphates; D051176:beta Catenin; C037178:phosphatidylinositol 4-phosphate; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D020764:cdc42 GTP-Binding Protein