Rho GTP exchange factor ARHGEF11 regulates the integrity of epithelial junctions by connecting ZO-1 and RhoA-myosin II signaling.
The organization of the apical junctional complex and its association with the cytoskeleton is essential for the function of epithelial cells. However, knowledge about the signaling pathways that regulate these processes is still fragmentary. Here we found that ARHGEF11, a member of the RGS-RhoGEF family, associates with tight junctions (TJs) by binding to ZO-1, but not to the highly homologous ZO-2, in polarized epithelial cells. In the early phases of cell-cell contact, ARHGEF11 was located at primordial adherens junctions, and then its localization was altered to TJs as epithelial polarity was established, much like ZO-1. Knockdown of ARHGEF11 reduced the phosphorylation of myosin light chain, retarding the assembly of cell-cell junctions and the development of the paracellular barrier. Furthermore, the simultaneous knockdown of ARHGEF11 and ZO-2 resulted in significant impairment of TJs and of the perijunctional actomyosin ring; similar defects arise when both ZO-1 and ZO-2 are depleted. These results suggest that ARHGEF11 mediates RhoA-myosin light chain signaling pathways at cell-cell junctions, functioning in cooperation with ZO-1, to regulate the paracellular barrier and the organization of the apical junctional complex and perijunctional actomyosin ring of epithelial cells.
Department of Biochemistry, School of Medicine, Dokkyo Medical University, Tochigi 321-0293 Japan. mitoh@dokkyomed.ac.jp
Masahiko
M
Itoh
Sachiko
S
Tsukita
Yuji
Y
Yamazaki
Hiroyuki
H
Sugimoto
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D024462:Myosin Type II / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism; D062826:Zonula Occludens-1 Protein; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
C574809:ARHGEF11 protein, mouse; D015820:Cadherins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D010750:Phosphoproteins; D064067:Rho Guanine Nucleotide Exchange Factors; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D024462:Myosin Type II; D020742:rhoA GTP-Binding Protein