title: Cadherin-6B proteolysis promotes the neural crest cell epithelial-to-mesenchymal transition through transcriptional regulation.
abstract: During epithelial-to-mesenchymal transitions (EMTs), cells disassemble cadherin-based junctions to segregate from the epithelia. Chick premigratory cranial neural crest cells reduce Cadherin-6B (Cad6B) levels through several mechanisms, including proteolysis, to permit their EMT and migration. Serial processing of Cad6B by a disintegrin and metalloproteinase (ADAM) proteins and γ-secretase generates intracellular C-terminal fragments (CTF2s) that could acquire additional functions. Here we report that Cad6B CTF2 possesses a novel pro-EMT role by up-regulating EMT effector genes in vivo. After proteolysis, CTF2 remains associated with β-catenin, which stabilizes and redistributes both proteins to the cytosol and nucleus, leading to up-regulation of β-catenin, CyclinD1, Snail2, and Snail2 promoter-based GFP expression in vivo. A CTF2 β-catenin-binding mutant, however, fails to alter gene expression, indicating that CTF2 modulates β-catenin-responsive EMT effector genes. Notably, CTF2 association with the endogenous Snail2 promoter in the neural crest is β-catenin dependent. Collectively, our data reveal how Cad6B proteolysis orchestrates multiple pro-EMT regulatory inputs, including CTF2-mediated up-regulation of the Cad6B repressor Snail2, to ensure proper cranial neural crest EMT.
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742.
authors.forename: Andrew T
authors.identifier: http://orcid.org/0000-0003-1812-1508
authors.initials: AT
authors.lastname: Schiffmacher
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742.
authors.forename: Vivien
authors.identifier: http://orcid.org/0000-0002-7554-8658
authors.initials: V
authors.lastname: Xie
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742 ltaney@umd.edu.
authors.forename: Lisa A
authors.identifier: http://orcid.org/0000-0002-8630-2514
authors.initials: LA
authors.lastname: Taneyhill
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030161:Avian Proteins / Q000737:chemistry / Q000378:metabolism*; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002645:Chickens; D002843:Chromatin / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D008954:Models, Biological; D009432:Neural Crest / Q000166:cytology*; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
chemical_list: D030161:Avian Proteins; D015820:Cadherins; D002843:Chromatin; D000071250:Snail Family Transcription Factors; D051176:beta Catenin; C094293:cad6B protein, Gallus gallus