Protein Ser/Thr phosphatase-6 is required for maintenance of E-cadherin at adherens junctions.
BACKGROUND
Epithelial tissues depend on intercellular homodimerization of E-cadherin and loss of E-cadherin is central to the epithelial to mesenchymal transition seen in multiple human diseases. Signaling pathways regulate E-cadherin function and cellular distribution via phosphorylation of the cytoplasmic region by kinases such as casein kinases but the protein phosphatases involved have not been identified.


RESULTS
This study shows protein Ser/Thr phosphatase-6 catalytic subunit (PP6c) is expressed in epithelial tissue and its mRNA and protein are robustly up-regulated in epithelial cell lines at high vs. low density. PP6c accumulates at adherens junctions, not tight junctions, co-immunoprecipitates with E-cadherin-catenin complexes without a canonical SAPS subunit, and associates directly with the E-cadherin cytoplasmic tail. Inducible shRNA knockdown of PP6c dispersed E-cadherin from the cell surface and this response was reversed by chemical inhibition of casein kinase-1 and prevented by alanine substitution of Ser846 in murine E-cadherin.


CONCLUSIONS
PP6c associates with E-cadherin in adherens junctions and is required to oppose casein kinase-1 to maintain cell surface localization of E-cadherin. There is feedback signaling to enhance PP6c transcription and boost protein levels in high density epithelial cells.
Center for Cell Signaling and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Box 800577, West Complex MSB 7225, Charlottesville, Virginia 22908, USA. db8g@virginia.edu.
Takashi
T
Ohama
Lifu
L
Wang
Erin M
EM
Griner
David L
DL
Brautigan
D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D019943:Amino Acid Substitution; D018938:Caco-2 Cells; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D047389:Casein Kinase I / Q000235:genetics* / Q000378:metabolism; D051177:Catenins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
D015820:Cadherins; D051177:Catenins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D047389:Casein Kinase I; D010749:Phosphoprotein Phosphatases; C106079:protein phosphatase 6