Glycogen synthase kinase-3β modulates notch signaling and stability

Daniel R. Foltz, Michelle C. Santiago, Bridget E. Berechid, Jeffrey S. Nye

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

Abstract

Notch receptors modulate transcriptional targets following the proteolytic release of the Notch intracellular domain (NotchIC). Phosphorylated forms of NotchIC have been identified within the nucleus [1 2] and have been associated with CSL members [3 4] as well as correlated with regions of the receptor that are required for activity [4 5]. Genetic studies have suggested that the Drosophila homolog of glycogen synthase kinase-3β (GSK3β) Shaggy may act as a positive modulator of the Notch signaling [6 7]. GSK3β is a serine/threonine kinase and is a component of the Wnt/wingless signaling cascade [8]. Here we observed that GSK3β was able to bind and phosphorylate NotchlIC in vitro and attenuation of GSK3β activity reduced phosphorylation of NotchIC in vivo. Functionally ligand-activated signaling through the endogenous Notch1 receptor was reduced in GSK3β null fibroblasts implying a positive role for GSK3β in mammalian Notch signaling. As a possible mechanistic explanation of the effect of GSK3β on Notch signaling we observed that inhibition of GSK3β shortened the half-life of Notch1IC. Conversely activated GSK3β reduced the quantity of Notch1IC that was degraded by the proteasome. These studies reveal that GSK3β modulates Notch1 signaling possibly through direct phosphorylation of the intracellular domain of Notch and that the activity of GSK3β protects the intracellular domain from proteasome degradation.

Original languageEnglish (US)
Pages (from-to)1006-1011
Number of pages6
JournalCurrent Biology
Volume12
Issue number12
DOIs
StatePublished - Jun 25 2002

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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