Dataset Information

AMP-activated protein kinase (AMPK) activation and glycogen synthase kinase-3? (GSK-3?) inhibition induce Ca2+-independent deposition of tight junction components at the plasma membrane.

ABSTRACT: Extracellular Ca(2+) is essential for the development of stable epithelial tight junctions. We find that in the absence of extracellular Ca(2+), AMP-activated protein kinase (AMPK) activation and glycogen synthase kinase (GSK)-3? inhibition independently induce the localization of epithelial tight junction components to the plasma membrane. The Ca(2+)-independent deposition of junctional proteins induced by AMPK activation and GSK-3? inhibition is independent of E-cadherin. Furthermore, the nectin-afadin system is required for the deposition of tight junction components induced by AMPK activation, but it is not required for that induced by GSK-3? inhibition. Phosphorylation studies demonstrate that afadin is a substrate for AMPK. These data demonstrate that two kinases involved in regulating cell growth and metabolism act through distinct pathways to influence the deposition of the components of epithelial tight junctions.

SUBMITTER: Zhang L

PROVIDER: S-EPMC3089531 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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AMP-activated protein kinase (AMPK) activation and glycogen synthase kinase-3β (GSK-3β) inhibition induce Ca2+-independent deposition of tight junction components at the plasma membrane.

Zhang Li L Jouret Francois F Rinehart Jesse J Sfakianos Jeff J Mellman Ira I Lifton Richard P RP Young Lawrence H LH Caplan Michael J MJ

The Journal of biological chemistry 20110307 19

Extracellular Ca(2+) is essential for the development of stable epithelial tight junctions. We find that in the absence of extracellular Ca(2+), AMP-activated protein kinase (AMPK) activation and glycogen synthase kinase (GSK)-3β inhibition independently induce the localization of epithelial tight junction components to the plasma membrane. The Ca(2+)-independent deposition of junctional proteins induced by AMPK activation and GSK-3β inhibition is independent of E-cadherin. Furthermore, the nect ...[more]

PMID: 21383016

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Project description:The Ca(2+)-sensing receptor (CaSR) belongs to the G-protein-coupled receptor superfamily and plays essential roles in divalent ion homeostasis and cell differentiation. Because extracellular Ca(2+) is essential for the development of stable epithelial tight junctions (TJs), we hypothesized that the CaSR participates in regulating TJ assembly. We first assessed the expression of the CaSR in Madin-Darby canine kidney (MDCK) cells at steady state and following manipulations that modulate TJ assembly. Next, we examined the effects of CaSR agonists and antagonists on TJ assembly. Immunofluorescence studies indicate that endogenous CaSR is located at the basolateral pole of MDCK cells. Stable transfection of human CaSR in MDCK cells further reveals that this protein co-distributes with β-catenin on the basolateral membrane. Switching MDCK cells from low-Ca(2+) medium to medium containing a normal Ca(2+) concentration significantly increases CaSR expression at both the mRNA and protein levels. Exposure of MDCK cells maintained in low-Ca(2+) conditions to the CaSR agonists neomycin, Gd(3+) or R-568 causes the transient relocation of the tight junction components ZO-1 and occludin to sites of cell-cell contact, while inducing no significant changes in the expression of mRNAs encoding junction-associated proteins. Stimulation of CaSR also increases the interaction between ZO-1 and the F-actin-binding protein I-afadin. This effect does not involve activation of the AMP-activated protein kinase. By contrast, CaSR inhibition by NPS-2143 significantly decreases interaction of ZO-1 with I-afadin and reduces deposition of ZO-1 at the cell surface following a Ca(2+) switch from 5 µM to 200 µM [Ca(2+)]e. Pre-exposure of MDCK cells to the cell-permeant Ca(2+) chelator BAPTA-AM, similarly prevents TJ assembly caused by CaSR activation. Finally, stable transfection of MDCK cells with a cDNA encoding a human disease-associated gain-of-function mutant form of the CaSR increases the transepithelial electrical resistance of these cells in comparison to expression of the wild-type human CaSR. These observations suggest that the CaSR participates in regulating TJ assembly.

Dataset Information

AMP-activated protein kinase (AMPK) activation and glycogen synthase kinase-3? (GSK-3?) inhibition induce Ca2+-independent deposition of tight junction components at the plasma membrane.

Publications

AMP-activated protein kinase (AMPK) activation and glycogen synthase kinase-3β (GSK-3β) inhibition induce Ca2+-independent deposition of tight junction components at the plasma membrane.

Similar Datasets

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