title: Regulation of Monocarboxylic Acid Transporter 1 Trafficking by the Canonical Wnt/β-Catenin Pathway in Rat Brain Endothelial Cells Requires Cross-talk with Notch Signaling.
abstract: The transport of monocarboxylate fuels such as lactate, pyruvate, and ketone bodies across brain endothelial cells is mediated by monocarboxylic acid transporter 1 (MCT1). Although the canonical Wnt/β-catenin pathway is required for rodent blood-brain barrier development and for the expression of associated nutrient transporters, the role of this pathway in the regulation of brain endothelial MCT1 is unknown. Here we report expression of nine members of the frizzled receptor family by the RBE4 rat brain endothelial cell line. Furthermore, activation of the canonical Wnt/β-catenin pathway in RBE4 cells via nuclear β-catenin signaling with LiCl does not alter brain endothelialMct1mRNA but increases the amount of MCT1 transporter protein. Plasma membrane biotinylation studies and confocal microscopic examination of mCherry-tagged MCT1 indicate that increased transporter results from reduced MCT1 trafficking from the plasma membrane via the endosomal/lysosomal pathway and is facilitated by decreased MCT1 ubiquitination following LiCl treatment. Inhibition of the Notch pathway by the γ-secretase inhibitorN-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butyl ester negated the up-regulation of MCT1 by LiCl, demonstrating a cross-talk between the canonical Wnt/β-catenin and Notch pathways. Our results are important because they show, for the first time, the regulation of MCT1 in cerebrovascular endothelial cells by the multifunctional canonical Wnt/β-catenin and Notch signaling pathways.
authors.affiliation: From the Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, Minnesota 55812 and zejian.liu@yale.edu.
authors.forename: Zejian
authors.identifier: http://orcid.org/0000-0002-5838-7653
authors.initials: Z
authors.lastname: Liu
authors.affiliation: From the Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, Minnesota 55812 and.
authors.forename: Mary
authors.initials: M
authors.lastname: Sneve
authors.affiliation: From the Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, Minnesota 55812 and.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Haroldson
authors.affiliation: the Department of Biology, Colorado State University, Pueblo, Colorado 81001.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Smith
authors.affiliation: From the Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, Minnesota 55812 and ldrewes@d.umn.edu.
authors.forename: Lester R
authors.identifier: http://orcid.org/0000-0002-7440-0387
authors.initials: LR
authors.lastname: Drewes
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism*; D027981:Symporters / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; D051880:Receptors, Notch; D027981:Symporters; D051176:beta Catenin; D000099233:Monocarboxylate Transport Protein 1
keywords: Notch pathway; RBE4; SLC16A1; Wnt pathway; blood-brain barrier; cross-talk; endocytosis; gene regulation; monocarboxylic acid transporter; ubiquitylation (ubiquitination)