Small C-terminal domain phosphatase enhances snail activity through dephosphorylation
Authors: B Mark Evers
Binhua P Zhou
Yadi Wu
Journal: Journal of Biological Chemistry (2009)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: E-cadherin; epithelial-mesenchymal transition (EMT); Snail; GSK-3beta; phosphorylation
Affiliations: Department of Pharmacology and Toxicology, the University of Texas Medical Branch, Galveston, Texas 77555, USA.

Abstract:  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. 

Retracted: No

PubPeer comments:
 ![file] There are undeclared splice site (in violet) in Figure 6A. Could authors provide an explanation, please? , 
 #1 We agreed that the first 4 lanes of Figure 6A were from different WB. In this experiment, we determined and compared the levels of protein stabilization of wild-type and three mutants of Snail by the treatment of proteasome inhibitor MG132 and phosphatase SCP. Specifically, we had 4 groups of samples, and each group contained 4 individual samples (represented as 4 lanes group in WB). Treated samples were directly compared with the un-treated control (sample 1 or lane 1 in each group) within each group. All samples were prepared under same experimental condition. Because we had total 16 samples (4 groups), and because the majority of SDS-PAGE apparatus can only hold up to 14 samples (one marker + 14 samples), we therefore had to run these samples on separate blots and merged the first group (first 4 lanes) with other groups in Figure 6A for easy visualization. Since results were compared within groups, thus, the conclusion will not be affected by this merge and we firmly stand for our conclusion. We had contacted the journal to seek whether we need to make a correction. In addition, we greatly appreciated the concern raised by the anonymous commenter. ,