Regulation of Monocarboxylic Acid Transporter 1 Trafficking by the Canonical Wnt/{beta}-catenin Pathway in Rat Brain Endothelial Cells, Requiring a Crosstalk with Notch Signaling [Signal Transduction]

February 12th, 2016 by Liu, Z., Sneve, M., Haroldson, T. A., Smith, J. P., Drewes, L. R.

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 (BBB) development and for the expression of associated nutrient transporters, the role of this pathway in 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 lithium chloride (LiCl) does not alter brain endothelial Mct1 mRNA, 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 inhibitor, DAPT, negated the upregulation of MCT1 by LiCl, thus demonstrating a crosstalk 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 multi-functional canonical Wnt/β-catenin and Notch signaling pathways.
  • Posted in Journal of Biological Chemistry, Publications
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