Glycogen synthase kinase-3β is a negative regulator of cardiomyocyte hypertrophy

Syed Haq, Gabriel Choukroun, Zhao Bin Kang, Hardeep Ranu, Takashi Matsui, Anthony Rosenzweig, Jeffrey D. Molkentin, Alessandro Alessandrini, James Woodgett, Roger Hajjar, Ashour Michael, Thomas Force

Research output: Contribution to journalArticlepeer-review

342 Scopus citations


Hypertrophy is a basic cellular response to a variety of stressors and growth factors, and has been best characterized in myocytes. Pathologic hypertrophy of cardiac myocytes leads to heart failure, a major cause of death and disability in the developed world. Several cytosolic signaling pathways have been identified that transduce prohypertrophic signals, but to date, little work has focused on signaling pathways that might negatively regulate hypertrophy. Herein, we report that glycogen synthase kinase-3β (GSK-3β), a protein kinase previously implicated in processes as diverse as development and tumorigenesis, is inactivated by hypertrophic stimuli via a phosphoinositide 3-kinase-dependent protein kinase that phosphorylates GSK-3β on ser 9. Using adenovirus-mediated gene transfer of GSK-3β containing a ser 9 to alanine mutation, which prevents inactivation by hypertrophic stimuli, we demonstrate that inactivation of GSK-3β is required for cardiomyocytes to undergo hypertrophy. Furthermore, our data suggest that GSK-3β regulates the hypertrophic response, at least in part, by modulating the nuclear/cytoplasmic partitioning of a member of the nuclear factor of activated T cells family of transcription factors. The identification of GSK-3β as a transducer of antihypertrophic signals suggests that novel therapeutic strategies to treat hypertrophic diseases of the heart could be designed that target components of the GSK-3 pathway.

Original languageEnglish
Pages (from-to)117-129
Number of pages13
JournalJournal of Cell Biology
Issue number1
StatePublished - 2 Oct 2000
Externally publishedYes


  • Adenovirus
  • Endothelin-1
  • Heart
  • Nuclear factor of activated T cells
  • Protein kinase B


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