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Kindlin 2 forms a transcriptional complex with ?-catenin and TCF4 to enhance Wnt signalling.

ABSTRACT: Kindlin 2, as a focal adhesion protein, controls integrin activation. However, the association of Kindlin 2 with cancer-related signalling pathways is unknown. Here we identified a new direct interaction between Kindlin 2 and the active ?-catenin. Importantly, Kindlin 2 forms a tripartite complex with ?-catenin and TCF4. Mechanistically, Kindlin 2 selectively strengthens the occupancy of ?-catenin on the Wnt target gene Axin2 and enhances Axin2 gene expression. Functionally, the ?-catenin-Axin2-Snail cascade is required for Kindlin 2-induced tumour cell invasion. Our data indicate that Kindlin 2 is a new regulator of Wnt signalling, providing a mechanistic insight into the role of Kindlin 2 in cancer progression.

SUBMITTER: Yu Y

PROVIDER: S-EPMC3410388 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Kindlin 2 forms a transcriptional complex with β-catenin and TCF4 to enhance Wnt signalling.

Yu Yu Y Wu Junzhou J Wang Yunling Y Zhao Ting T Ma Bo B Liu Yuqing Y Fang Weigang W Zhu Wei-Guo WG Zhang Hongquan H

EMBO reports 20120615 8

Kindlin 2, as a focal adhesion protein, controls integrin activation. However, the association of Kindlin 2 with cancer-related signalling pathways is unknown. Here we identified a new direct interaction between Kindlin 2 and the active β-catenin. Importantly, Kindlin 2 forms a tripartite complex with β-catenin and TCF4. Mechanistically, Kindlin 2 selectively strengthens the occupancy of β-catenin on the Wnt target gene Axin2 and enhances Axin2 gene expression. Functionally, the β-catenin-Axin2- ...[more]

PMID: 22699938

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Project description:Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing ?-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 ?-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

Kindlin 2 forms a transcriptional complex with ?-catenin and TCF4 to enhance Wnt signalling.

Publications

Kindlin 2 forms a transcriptional complex with β-catenin and TCF4 to enhance Wnt signalling.

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