title: Tara up-regulates E-cadherin transcription by binding to the Trio RhoGEF and inhibiting Rac signaling.
abstract: The spatiotemporal regulation of E-cadherin expression is important during body plan development and carcinogenesis. We found that Tara (Trio-associated repeat on actin) is enriched in cadherin-based adherens junctions (AJs), and its knockdown in MDCK cells (Tara-KD cells) significantly decreases the expression of E-cadherin. Tara-KD activates Rac1 through the Trio RhoGEF, which binds to E-cadherin and subsequently increases the phosphorylation of p38 and Tbx3, a transcriptional E-cadherin repressor. Accordingly, the decrease in E-cadherin expression is abrogated by ITX3 and SB203580 (specific inhibitors of Trio RhoGEF and p38MAPK, respectively), and by dephosphomimetic Tbx3. Despite the decreased E-cadherin expression, the Tara-KD cells do not undergo an epithelial-mesenchymal transition and remain as an epithelial cell sheet, presumably due to the concomitant up-regulation of cadherin-6. Tara-KD reduces the actin-belt density in the circumferential ring, and the cells form flattened cysts, suggesting that Tara functions to modulate epithelial cell sheet formation and integrity by up-regulating E-cadherin transcription.
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yano
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Adachi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Okawa
authors.forename: Philippe
authors.initials: P
authors.lastname: Fort
authors.forename: Masami
authors.initials: M
authors.lastname: Uji
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Tsukita
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tsukita
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism*; D002460:Cell Line; D004285:Dogs; D058750:Epithelial-Mesenchymal Transition; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014158:Transcription, Genetic; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D015820:Cadherins; D020662:Guanine Nucleotide Exchange Factors; C543416:ITX3 compound; D007093:Imidazoles; D008840:Microfilament Proteins; D011725:Pyridines; D064067:Rho Guanine Nucleotide Exchange Factors; D020825:T-Box Domain Proteins; C550098:TRIOBP protein, mouse; D013844:Thiazoles; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; C093642:SB 203580