Membrane‐tethered syntaxin‐4 locally abrogates E‐cadherin function and activates Smad signals, contributing to asymmetric mammary epithelial morphogenesis. Issue 9 (16th May 2018)

• Record Type: Journal Article
• Authors: Hirose, Yuina; Shirai, Kota; Hirai, Yohei
• Is Part Of: Journal of cellular biochemistry. Volume 119:Issue 9(2018)
• Page Start: 7525
• Page End: 7539
• Publication Date: 2018-05-16
• Subjects: asymmetric structure -- E‐cadherin -- epimorphin -- epithelial‐mesenchymal transition -- mammary gland -- Smad; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.27064
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: Spatial and temporal epithelial‐mesenchymal transition (EMT) is a critical event for the generation of asymmetric epithelial architectures. We found that only restricted cell populations in the morphogenic mammary epithelia extrude syntaxin‐4, a plasmalemmal t‐SNARE protein, and that epithelial cell clusters with artificial heterogenic presentation of extracellular syntaxin‐4 undergo asymmetric morphogenesis. A previous study revealed that inducible expression of cell surface syntaxin‐4 causes EMT‐like cell behaviors in the clonal mammary epithelial cells, where laminin‐mediated signals were abolished so that cells readily succumb to initiate EMT. The present study added new mechanistic insight into syntaxin‐4‐driven EMT‐like cell behaviors. Extracellular syntaxin‐4 directly perturbs E‐cadherin‐mediated epithelial cell‐cell adhesion and activates Smad signals. We found that the epithelial cells activated Smad2/3 upon induction of expression of extracellular syntaxin‐4, leading to the upregulation of certain transcriptional targets of these TGF‐β signaling mediators. Intriguingly, however, mRNA expression of canonical EMT initiators, such as Snail and Slug, was unchanged. In addition, E‐cadherin protein was steeply decreased, yet its transcriptional expression remained constant for a couple of days. We found that extracellular syntaxin‐4 directly bound to E‐cadherin and sequestered β‐catenin from cell‐cell contact sites, perturbing intercellular adhesive property. The functional ablation of E‐cadherin by syntaxin‐4 was further validated by L cells with stably expressing E‐cadherin, in which cells shows intercellular adhesive property solely by E‐cadherin. These results underline the role of local exportation of syntaxin‐4 for onset of complex epithelial morphogenesis. Abstract : Mammary epithelia appeared to create a pre‐morphogenic niche for asymmetric epithelial morphogenesis with local extrusion of a t‐SNARE protein syntaxin‐4. We show that mammary epithelia locally extrude syntaxin‐4 subpopulation, which hinders both E‐cadherin‐mediated intercellular adhesion and laminin‐mediated cell‐substrate interaction, leading to local epithelial‐mesenchymal transition.