Stabilization of beta-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth.
beta-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 beta-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 beta-catenin and, if so, what factors mediate that stabilization and what biologic processes might be regulated. Herein we report that beta-catenin is stabilized in cardiomyocytes after these cells have been exposed to hypertrophic stimuli in culture or in vivo. The mechanism by which beta-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 beta-catenin, the mechanism by which this occurs involves the recruitment of activated PKB to the beta-catenin-degradation complex. PKB stabilizes the complex and phosphorylates glycogen synthase kinase-3 within the complex, inhibiting its activity directed at beta-catenin. Finally, we demonstrate via adenoviral gene transfer that beta-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, beta-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.
Haq
Syed
S
Molecular Cardiology Research Institute, Tufts-New England Medical Center, and Tufts University School of Medicine, Boston, MA 02111, USA. shaq@tufts-nemc.org
Michael
Ashour
A
Andreucci
Michele
M
Bhattacharya
Kausik
K
Dotto
Paolo
P
Walters
Brian
B
Woodgett
James
J
Kilter
Heiko
H
Force
Thomas
T
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004355:Drug Stability; D019332:Endothelin-1 / Q000494:pharmacology; D018014:Gene Transfer Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006984:Hypertrophy; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D019332:Endothelin-1; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D020962:Heterotrimeric GTP-Binding Proteins