The RNA-Binding Protein KSRP Promotes Decay of β-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling
| Autor: | Marco Ponassi, Tina Ruggiero, Paola Briata, Michele Trabucchi, Roberto Gherzi, Khalid S.A. Khabar, Giorgio Corte, Christoph Moroni, Ching Yi Chen, Jens S. Andersen |
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| Rok vydání: | 2006 |
| Předmět: |
Eukaryotes
RNA Stability RNA-binding protein Mice chemistry.chemical_compound 0302 clinical medicine 1-Phosphatidylinositol 3-Kinase Insulin Phosphorylation Biology (General) beta Catenin Mammals Genetics 0303 health sciences General Neuroscience Wnt signaling pathway RNA-Binding Proteins Mus (Mouse) 3. Good health Cell biology 030220 oncology & carcinogenesis Vertebrates Signal transduction General Agricultural and Biological Sciences Protein Binding Signal Transduction Research Article QH301-705.5 Phosphatidylinositol 3-Kinases Biology General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Humans Animals RNA Messenger Phosphatidylinositol Molecular Biology Protein kinase B 030304 developmental biology Messenger RNA General Immunology and Microbiology Enzyme Activation Wnt Proteins 14-3-3 Proteins Gene Expression Regulation chemistry Trans-Activators Proto-Oncogene Proteins c-akt Developmental Biology |
| Zdroj: | PLoS Biology PLoS Biology, Vol 5, Iss 1, p e5 (2006) Gherzi, R, Trabucchi, M, Ponassi, M, Ruggiero, T, Corte, G, Moroni, C, Chen, C-Y, Khabar, K S, Andersen, J S & Briata, P 2006, ' The RNA-binding protein KSRP promotes decay of beta-catenin mRNA and is inactivated by PI3K-AKT signaling ', PLoS-Biology, vol. 5, no. 1, pp. 82-95 . https://doi.org/10.1371/journal.pbio.0050005 |
| ISSN: | 1545-7885 |
| DOI: | 10.1371/journal.pbio.0050005 |
| Popis: | β-catenin plays an essential role in several biological events including cell fate determination, cell proliferation, and transformation. Here we report that β-catenin is encoded by a labile transcript whose half-life is prolonged by Wnt and phosphatidylinositol 3-kinase–AKT signaling. AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRP's ability to promote rapid mRNA decay. Our results uncover an unanticipated level of control of β-catenin expression pointing to KSRP as a required factor to ensure rapid degradation of β-catenin in unstimulated cells. We propose KSRP phosphorylation as a link between phosphatidylinositol 3-kinase–AKT signaling and β-catenin accumulation. Author Summary During mammalian development and adulthood, β-catenin regulates the transcription of a family of genes with multiple essential roles in cell proliferation and differentiation. β-catenin also plays a role in cancer when it carries mutations that result in uncontrolled β-catenin function. Here, we report that the lifetime of the β-catenin–encoding transcript is under regulatory control. We show that specific cellular signals relevant to proper mammalian development and implicated in tumor formation can prolong β-catenin transcript half-life, leading to the accumulation of β-catenin protein. We identify a molecular mechanism for this prolongation by showing that a protein factor responsible for β-catenin transcript instability (and thus degradation) is impaired by phosphorylation, a chemical modification. When this factor is impaired, β-catenin mRNA and protein accumulate. Our results point to an unanticipated control of β-catenin levels through regulation of its transcript half-life in response to signals related to proliferation and differentiation. The authors show that the half-life of β-catenin mRNA is prolonged by PI3K-AKT signaling, revealing a new level of control on β-catenin. |
| Databáze: | OpenAIRE |
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