Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: Functional effects in apoptosis

Gordon P. Meares, Richard S. Jope

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Mechanisms regulating the nuclear localization of glycogen synthase kinase-3β (GSK3β) remained enigmatic despite the crucial regulation by nuclear GSK3β of important cellular functions. These include regulation of gene expression, cell cycle progression, and apoptosis, achieved by the phosphorylation by GSK3 of nuclear substrates (e.g. numerous transcription factors). We resolved this mechanism by identifying a bipartite nuclear localization sequence (NLS) that is necessary for the nuclear accumulation of GSK3β and is sufficient to drive yellow fluorescent protein into the nucleus. Despite the NLS, most GSK3β is cytosolic, sequestered in protein complexes that, although still mobile in the cytosol, block the NLS. Conditions promoting nuclear translocation of GSK3β release it from cytosolic complexes, allowing the NLS to direct nuclear import. Using this information to prepare a nucleus-excluded active GSK3 construct, we found that the antiapoptotic effect of GSK3β in tumor necrosis factor-induced apoptosis is mediated by cytosolic, not nuclear, GSK3β. Identification of a GSK3β NLS allows new strategies to decipher and manipulate its subcellular actions regulating gene expression and apoptosis and its involvement in diseases.

Original languageEnglish (US)
Pages (from-to)16989-17001
Number of pages13
JournalJournal of Biological Chemistry
Volume282
Issue number23
DOIs
StatePublished - Jun 8 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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