Functional regulation of Slug / Snail2 is dependent on GSK‐3β‐mediated phosphorylation

Abstract

Snail family proteins regulate transcription of molecules for cell-cell adhesion during epithelial-mesenchymal transition (EMT). Based on putative glycogen synthase kinase 3β (GSK-3β) phosphorylation sites within the Slug/Snail2, we explored the significance of GSK-3β-mediated phosphorylation in Slug/Snail2 expression during EMT. Mutation of the putative GSK-3β phosphorylation sites (S92/96A or S100/104A) enhanced the Slug/Snail2-mediated EMT properties of E-cadherin repression and vimentin induction, compared with wild-type Slug/Snail2. S92/96A mutation inhibited degradation of Slug/Snail2 and S100/104A mutation extended nuclear stabilization. Inhibition of GSK-3β activity caused similar effects, as did the phosphorylation mutations. Thus, our study suggests that GSK-3β-mediated phosphorylation of Slug/Snail2 controls its turnover and localization during EMT.

Neural crest–derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septation

“…Moreover, SLUG staining, rather than being nuclear, appeared predominantly cytoplasmic in the OFT endothelium of Nrp1-null mutants ( Figure 10D). A similar staining pattern was previously observed in cells with impaired SLUG phosphorylation (47), raising the possibility that cytoplasmic SLUG staining in Nrp1-null OFTs reflects dysregulated signaling. mutants had normal cardiac NCC migration into the OFT disagrees with prior studies in chick, in which siRNA-mediated NRP1 targeting impaired this process (14).…”

Immunohistological Insight into the Correlation between Neuropilin-1 and Epithelial-Mesenchymal Transition Markers in Epithelial Ovarian Cancer

“…Although it has been shown that E-cadherin is repressed by Slug (Kim et al 2012;Peinado et al 2007;Vergara et al 2010;Yoshida et al 2009), some studies show that EOC cells do not always undergo a full and classical EMT (Davidson et al 2012;Peinado et al 2007). For instance, E-cadherin was found to be up-regulated in some ovarian neoplasm cells (Davidson et al 2012;Rodriguez et al 2012;Sundfeldt et al 1997).…”

Regulation of the protein stability of EMT transcription factors

“…Snail2 also contains 2 GSK-3b motifs inside the Slug domain in a recently identified Serine rich region that alike Snail1 affects ubiquitination and degradation by b-TrCP1, although this sequence does not contain the classical b-TrCP1 destruction motif. 84,85 Besides phosphorylation of the substrate, an active SCFb-TrCP1 complex requires the neddylation (incorporation of the small protein Nedd8) of Cul1 by a Nedd8-E3 ligase. 86 Interestingly, TNF-a promotes the induction of the COP9 signalosome 2 protein (CSN2) that removes Nedd8 (or reverses neddylation) from cullins increasing Snail1 stabilization during inflammation.…”