Stabilization of β-Catenin by a Wnt-Independent Mechanism Regulates Cardiomyocyte Growth

β-Catenin is a transcriptional activator that regulates embryonic development as part of the Wnt pathway and also plays a role in tumorigenesis. The mechanisms leading to Wnt-induced stabilization of β-catenin, which results in its translocation to the nucleus and activation of transcription, have b...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2003-04, Vol.100 (8), p.4610-4615
Main Authors: Haq, Syed, Michael, Ashour, Andreucci, Michele, Bhattacharya, Kausik, Dotto, Paolo, Walters, Brian, Woodgett, James, Kilter, Heiko, Force, Thomas
Format: Article
Language:English
Subjects:
Animals
Antibodies
beta Catenin
Biological Sciences
Cell cycle
Cell Division - physiology
Cell growth
Cells
Cells, Cultured
Cellular biology
Cytoskeletal Proteins - genetics
Cytoskeletal Proteins - metabolism
Drug Stability
Endothelin-1 - pharmacology
Enzymes
Gene expression regulation
Gene Transfer Techniques
Glycogen Synthase Kinase 3 - antagonists & inhibitors
Heterotrimeric GTP-Binding Proteins - metabolism
Hypertrophy
Myocardium
Myocytes, Cardiac - cytology
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Phenylephrine - pharmacology
Phosphorylation
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Rats
Receptors, Cell Surface - metabolism
Signal Transduction
T lymphocytes
Trans-Activators - genetics
Trans-Activators - metabolism
Vehicles
Wnt Proteins
Zebrafish Proteins
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Summary:β-Catenin is a transcriptional activator that regulates embryonic development as part of the Wnt pathway and also plays a role in tumorigenesis. The mechanisms leading to Wnt-induced stabilization of β-catenin, which results in its translocation to the nucleus and activation of transcription, have been an area of intense interest. However, it is not clear whether stimuli other than Wnts can lead to important stabilization of β-catenin and, if so, what factors mediate that stabilization and what biologic processes might be regulated. Herein we report that β-catenin is stabilized in cardiomyocytes after these cells have been exposed to hypertrophic stimuli in culture or in vivo. The mechanism by which β-catenin is stabilized is distinctly different from that used by Wnt signaling. Although, as with Wnt signaling, inhibition of glycogen synthase kinase-3 remains central to hypertrophic stimulus-induced stabilization of β-catenin, the mechanism by which this occurs involves the recruitment of activated PKB to the β-catenin-degradation complex. PKB stabilizes the complex and phosphorylates glycogen synthase kinase-3 within the complex, inhibiting its activity directed at β-catenin. Finally, we demonstrate via adenoviral gene transfer that β-catenin is both sufficient to induce growth in cardiomyocytes in culture and in vivo and necessary for hypertrophic stimulus-induced growth. Thus, in these terminally differentiated cells, β-catenin is stabilized by hypertrophic stimuli acting via heterotrimeric G protein-coupled receptors. The stabilization occurs via a unique Wnt-independent mechanism and results in cellular growth.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0835895100