Activation of Wnt signaling by chemically induced dimerization of LRP5 disrupts cellular homeostasis
2012
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- Autor(en) / Beteiligte
- Titel
- Activation of Wnt signaling by chemically induced dimerization of LRP5 disrupts cellular homeostasis
- Ist Teil von
- PloS one, 2012-01, Vol.7 (1), p.e30814-e30814
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Wnt signaling is crucial for a variety of biological processes, including body axis formation, planar polarity, stem cell maintenance and cellular differentiation. Therefore, targeted manipulation of Wnt signaling in vivo would be extremely useful. By applying chemical inducer of dimerization (CID) technology, we were able to modify the Wnt co-receptor, low-density lipoprotein (LDL)-receptor-related protein 5 (LRP5), to generate the synthetic ligand inducible Wnt switch, iLRP5. We show that iLRP5 oligomerization results in its localization to disheveled-containing punctate structures and sequestration of scaffold protein Axin, leading to robust β-catenin-mediated signaling. Moreover, we identify a novel LRP5 cytoplasmic domain critical for its intracellular localization and casein kinase 1-dependent β-catenin signaling. Finally, by utilizing iLRP5 as a Wnt signaling switch, we generated the Ubiquitous Activator of β-catenin (Ubi-Cat) transgenic mouse line. The Ubi-Cat line allows for nearly ubiquitous expression of iLRP5 under control of the H-2K(b) promoter. Activation of iLRP5 in isolated prostate basal epithelial stem cells resulted in expansion of p63(+) cells and development of hyperplasia in reconstituted murine prostate grafts. Independently, iLRP5 induction in adult prostate stroma enhanced prostate tissue regeneration. Moreover, induction of iLRP5 in male Ubi-Cat mice resulted in prostate tumor progression over several months from prostate hyperplasia to adenocarcinoma. We also investigated iLRP5 activation in Ubi-Cat-derived mammary cells, observing that prolonged activation results in mammary tumor formation. Thus, in two distinct experimental mouse models, activation of iLRP5 results in disruption of tissue homeostasis, demonstrating the utility of iLRP5 as a novel research tool for determining the outcome of Wnt activation in a precise spatially and temporally determined fashion.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0030814Titel-ID: cdi_plos_journals_1323440252
- Format
- –
- Schlagworte
- Activation, Adaptor Proteins, Signal Transducing - metabolism, Adenocarcinoma, Amino Acid Sequence, Androgens, Animal genetic engineering, Animal models, Animals, Axin Protein - metabolism, beta Catenin - metabolism, Biochemistry, Biological activity, Biology, Breast cancer, Casein, Casein kinase I, Casein Kinase I - metabolism, Cell differentiation, Cellular biology, Development and progression, Dimerization, Dishevelled Proteins, Disruption, Drosophila melanogaster, Epithelial Cells - cytology, Epithelial Cells - metabolism, Female, Gene expression, Genetic engineering, Grafts, Heparan sulfate, Histocompatibility antigen H-2, Homeostasis, House mouse, Humans, Hyperplasia, Immunology, Insects, Intracellular signalling, Intracellular Space - metabolism, Kinases, Ligands, Localization, Low density lipoprotein, Low Density Lipoprotein Receptor-Related Protein-5 - metabolism, Low density lipoproteins, LRP5 protein, Male, Mammary gland, Mammary Neoplasms, Animal - pathology, Medicine, Membrane Microdomains - metabolism, Metastasis, Mice, Molecular biology, Molecular Sequence Data, Oligomerization, Oligomers, Pathology, Phosphoproteins - metabolism, Phosphorylation, Polarity, Prostate, Prostate - pathology, Prostate - transplantation, Prostate cancer, Protein Binding, Protein Multimerization, Protein Transport, Proteins, Receptor density, Regeneration, Rodents, Stem cell transplantation, Stem cells, Stroma, Stromal Cells - metabolism, Stromal Cells - pathology, Structure-Activity Relationship, Tissue engineering, Transgenic mice, Tumor Suppressor Proteins - metabolism, Tumors, Wnt protein, Wnt Signaling Pathway, β-Catenin