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JNK phosphorylates beta-catenin and regulates adherens junctions.

ABSTRACT: The c-Jun amino-terminal kinase (JNK) is an important player in inflammation, proliferation, and apoptosis. More recently, JNK was found to regulate cell migration by phosphorylating paxillin. Here, we report a novel role of JNK in cell adhesion. Specifically, we provide evidence that JNK binds to E-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by GSK-3beta. Inhibition of JNK kinase activity using dominant-negative constructs reduces phosphorylation of beta-catenin and promotes localization of E-cadherin/beta-catenin complex to cell-cell contact sites. Conversely, activation of JNK induces beta-catenin phosphorylation and disruption of cell contacts, which are prevented by JNK siRNA. We propose that JNK binds to beta-catenin and regulates formation of adherens junctions, ultimately controlling cell-to-cell adhesion.

SUBMITTER: Lee MH

PROVIDER: S-EPMC2774999 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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JNK phosphorylates beta-catenin and regulates adherens junctions.

Lee Meng-Horng MH Koria Piyush P Qu Jun J Andreadis Stelios T ST

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20090810 11

The c-Jun amino-terminal kinase (JNK) is an important player in inflammation, proliferation, and apoptosis. More recently, JNK was found to regulate cell migration by phosphorylating paxillin. Here, we report a novel role of JNK in cell adhesion. Specifically, we provide evidence that JNK binds to E-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by GSK-3beta. Inhibition of JNK kinase activity using dominant-negative cons ...[more]

PMID: 19667122

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JNK regulates binding of alpha-catenin to adherens junctions and cell-cell adhesion.

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Cadherin-bound beta-catenin feeds into the Wnt pathway upon adherens junctions dissociation: evidence for an intersection between beta-catenin pools.

Project description:Beta-catenin is an essential component of two cellular systems: cadherin-based adherens junctions (AJ) and the Wnt signaling pathway. A functional or physical connection between these beta-catenin pools has been suggested in previous studies, but not conclusively demonstrated to date. To further examine this intersection, we treated A431 cell colonies with lysophosphatidic acid (LPA), which forces rapid and synchronized dissociation of AJ. A combination of immunostaining, time-lapse microscopy using photoactivatable-GFP-tagged beta-catenin, and image analyses indicate that the cadherin-bound pool of beta-catenin, internalized together with E-cadherin, accumulates at the perinuclear endocytic recycling compartment (ERC) upon AJ dissociation, and can be translocated into the cell nucleus upon Wnt pathway activation. These results suggest that the ERC may be a site of residence for beta-catenin destined to enter the nucleus, and that dissociation of AJ may influence beta-catenin levels in the ERC, effectively affecting beta-catenin substrate levels available downstream for the Wnt pathway. This intersection provides a mechanism for integrating cell-cell adhesion with Wnt signaling and could be critical in developmental and cancer processes that rely on beta-catenin-dependent gene expression.

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Project description:Endothelial barrier integrity is ensured by the stability of the adherens junction (AJ) complexes comprised of vascular endothelial (VE)-cadherin as well as accessory proteins such as β-catenin and p120-catenin. Disruption of the endothelial barrier due to disassembly of AJs results in tissue edema and the influx of inflammatory cells. Using three-dimensional structured illumination microscopy, we observe that the mitochondrial protein Mitofusin-2 (Mfn2) co-localizes at the plasma membrane with VE-cadherin and β-catenin in endothelial cells during homeostasis. Upon inflammatory stimulation, Mfn2 is sulfenylated, the Mfn2/β-catenin complex disassociates from the AJs and Mfn2 accumulates in the nucleus where Mfn2 negatively regulates the transcriptional activity of β-catenin. Endothelial-specific deletion of Mfn2 results in inflammatory activation, indicating an anti-inflammatory role of Mfn2 in vivo. Our results suggest that Mfn2 acts in a non-canonical manner to suppress the inflammatory response by stabilizing cell-cell adherens junctions and by binding to the transcriptional activator β-catenin.

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Formation of E-cadherin/beta-catenin-based adherens junctions in hepatocytes requires serine-10 in p27(Kip1).

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| S-EPMC194899 | biostudies-other

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