Dataset Information

A p38 Mitogen-Activated Protein Kinase-Regulated Myocyte Enhancer Factor 2-?-Catenin Interaction Enhances Canonical Wnt Signaling.

ABSTRACT: Canonical Wnt/?-catenin signaling plays a major role in various biological contexts, such as embryonic development, cell proliferation, and cancer progression. Previously, a connection between p38 mitogen-activated protein kinase (MAPK) signaling and Wnt-mediated activation of ?-catenin was implied but poorly understood. In the present study, we investigated potential cross talk between p38 MAPK and Wnt/?-catenin signaling. Here we show that a loss of p38 MAPK ?/? function reduces ?-catenin nuclear accumulation in Wnt3a-stimulated primary vascular smooth muscle cells (VSMCs). Conversely, active p38 MAPK signaling increases ?-catenin nuclear localization and target gene activity in multiple cell types. Furthermore, the effect of p38 MAPK ?/? on ?-catenin activity is mediated through phosphorylation of a key p38 MAPK target, myocyte enhancer factor 2 (MEF2). Here we report a p38 MAPK-mediated, phosphorylation-dependent interaction between MEF2 and ?-catenin in multiple cell types and primary VSMCs that results in (i) increased ?-catenin nuclear retention, which is reversed by small interfering RNA (siRNA)-mediated MEF2 gene silencing; (ii) increased activation of MEF2 and Wnt/?-catenin target genes; and (iii) increased Wnt-stimulated cell proliferation. These observations provide mechanistic insight into a fundamental level of cross talk between p38 MAPK/MEF2 signaling and canonical Wnt signaling.

SUBMITTER: Ehyai S

PROVIDER: S-EPMC4719302 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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A p38 Mitogen-Activated Protein Kinase-Regulated Myocyte Enhancer Factor 2-β-Catenin Interaction Enhances Canonical Wnt Signaling.

Ehyai Saviz S Dionyssiou Mathew G MG Gordon Joseph W JW Williams Declan D Siu K W Michael KW McDermott John C JC

Molecular and cellular biology 20151109 2

Canonical Wnt/β-catenin signaling plays a major role in various biological contexts, such as embryonic development, cell proliferation, and cancer progression. Previously, a connection between p38 mitogen-activated protein kinase (MAPK) signaling and Wnt-mediated activation of β-catenin was implied but poorly understood. In the present study, we investigated potential cross talk between p38 MAPK and Wnt/β-catenin signaling. Here we show that a loss of p38 MAPK α/β function reduces β-catenin nucl ...[more]

PMID: 26552705

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Project description:Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.

Dataset Information

A p38 Mitogen-Activated Protein Kinase-Regulated Myocyte Enhancer Factor 2-?-Catenin Interaction Enhances Canonical Wnt Signaling.

Publications

A p38 Mitogen-Activated Protein Kinase-Regulated Myocyte Enhancer Factor 2-β-Catenin Interaction Enhances Canonical Wnt Signaling.

Similar Datasets

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