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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 8; pp. 4610 - 4615
• Main Authors: Haq, Syed, Michael, Ashour, Andreucci, Michele, Bhattacharya, Kausik, Dotto, Paolo, Walters, Brian, Woodgett, James, Kilter, Heiko, Force, Thomas
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15.04.2003; National Acad Sciences; The National Academy of Sciences
• 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
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0835895100

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.