Stabilization of β-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth

Abstract

␤-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 ␤-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 ␤-catenin and, if so, what factors mediate that stabilization and what biologic processes might be regulated. Herein we report that ␤-catenin is stabilized in cardiomyocytes after these cells have been exposed to hypertrophic stimuli in culture or in vivo. The mechanism by which ␤-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 ␤-catenin, the mechanism by which this occurs involves the recruitment of activated PKB to the ␤-catenin-degradation complex. PKB stabilizes the complex and phosphorylates glycogen synthase kinase-3 within the complex, inhibiting its activity directed at ␤-catenin. Finally, we demonstrate via adenoviral gene transfer that ␤-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, ␤-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.

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

“…β-catenin is also known to be phosphorylated by GSK-3β at another serine residue (Ser 33/37 ) followed by ubiquitination mediated degradation. 26,27 However, no band corresponding to phospho-Ser 33/37 was detected when MG132 pre-treated infected macrophages was subjected to Western blot analysis with anti-phospho-Ser 33/37 antibody (Figure 4c). This is in line with our earlier observation that GSK-3β remains inactive during infection (Figure 2a), thereby gets prevented from phosphorylating β-catenin.…”

Cardiac-specific haploinsufficiency of β-catenin attenuates cardiac hypertrophy but enhances fetal gene expression in response to aortic constriction

“…GSK-3ß activity is controlled by several signaling pathways and primarily regulated by inactivation. In cardiac myocytes, GSK-3ß is mainly regulated by Akt, but not Wnt/Wingless signaling pathway [3]. Akt phosphorylates GSK-3β and inhibits its activity, thereby stabilizing β-catenin and increasing its free cytoplasmic level.…”

“…Akt phosphorylates GSK-3β and inhibits its activity, thereby stabilizing β-catenin and increasing its free cytoplasmic level. The inhibition of GSK-3ß activity is required for cardiac hypertrophy induced by pressure overload and calcineurin activation [3,4]. Constitutively active GSK-3β attenuates cardiac hypertrophy by phosphorylating the nuclear factor of activated T cells (NFAT) and inhibiting its nuclear translocation.…”

“…The cytoplasmic level of β-catenin is increased in cultured neonatal cardiac myocytes by hypertrophic stimuli and in adult animals after transverse aortic constriction (TAC) [3]. More importantly, adenoviral infection of adult myocardium with a stabilized form of β-catenin induces cardiac hypertrophy [3].…”

“…More importantly, adenoviral infection of adult myocardium with a stabilized form of β-catenin induces cardiac hypertrophy [3]. Thus stabilization of β-catenin in cardiac myocytes is sufficient to cause cardiac hypertrophy.…”