Small C-terminal domain phosphatase enhances snail activity through dephosphorylation.
Down-regulation of E-cadherin plays an important role in epithelial-mesenchymal transition (EMT), which is critical in normal development and disease states such as tissue fibrosis and metastasis. Snail, a key transcription repressor of E-cadherin, is a labile protein with a short half-life and is regulated through phosphorylation, ubiquitination, and degradation. Previously, we showed that GSK-3beta phosphorylated two stretches of serine residues within the nuclear export signal and the destruction box of Snail, provoking its cytoplasmic export for ubiquitin-mediated proteasome degradation. However, the mechanism of Snail dephosphorylation and the identity of the Snail-specific phosphatase remain elusive. Using a functional genomic screening, we found that the small C-terminal domain phosphatase (SCP) is a specific phosphatase for Snail. SCP interacted and co-localized with Snail in the nucleus. We also found that SCP expression induced Snail dephosphorylation and stabilization in vitro and in vivo. However, a catalytically inactive mutant of SCP had no effect on Snail. Furthermore, we found that Snail stabilization induced by SCP enhanced snail activity in the suppression of E-cadherin and increased cell migration. Thus, our findings indicate that SCP functions as a Snail phosphatase to control its phosphorylation and stabilization, and our study provides novel insights for the regulation of Snail during EMT and cancer metastasis.
Wu
Yadi
Y
Departments of Pharmacology and Toxicology, and Surgery, and Sealy Center for Cancer Cell Biology, the University of Texas Medical Branch, Galveston, Texas 77555; Departments of Pharmacology and Toxicology, and Surgery, and Sealy Center for Cancer Cell Biology, the University of Texas Medical Branch, Galveston, Texas 77555.
Evers
B Mark
BM
Departments of Pharmacology and Toxicology, and Surgery, and Sealy Center for Cancer Cell Biology, the University of Texas Medical Branch, Galveston, Texas 77555; Departments of Pharmacology and Toxicology, and Surgery, and Sealy Center for Cancer Cell Biology, the University of Texas Medical Branch, Galveston, Texas 77555.
Zhou
Binhua P
BP
Departments of Pharmacology and Toxicology, and Surgery, and Sealy Center for Cancer Cell Biology, the University of Texas Medical Branch, Galveston, Texas 77555; Departments of Pharmacology and Toxicology, and Surgery, and Sealy Center for Cancer Cell Biology, the University of Texas Medical Branch, Galveston, Texas 77555. Electronic address: bpzhou@utmb.edu.
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002465:Cell Movement / Q000502:physiology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D049790:Nuclear Export Signals / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D013379:Substrate Specificity / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D049790:Nuclear Export Signals; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025801:Ubiquitin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D010749:Phosphoprotein Phosphatases; D046988:Proteasome Endopeptidase Complex