Glycogen synthase kinase-3beta modulates notch signaling and stability.
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 and have been associated with CSL members, as well as correlated with regions of the receptor that are required for activity. Genetic studies have suggested that the Drosophila homolog of glycogen synthase kinase-3beta (GSK3beta), Shaggy, may act as a positive modulator of the Notch signaling. GSK3beta is a serine/threonine kinase and is a component of the Wnt/wingless signaling cascade. Here, we observed that GSK3beta was able to bind and phosphorylate Notch1IC in vitro, and attenuation of GSK3beta activity reduced phosphorylation of NotchIC in vivo. Functionally, ligand-activated signaling through the endogenous Notch1 receptor was reduced in GSK3beta null fibroblasts, implying a positive role for GSK3beta in mammalian Notch signaling. As a possible mechanistic explanation of the effect of GSK3beta on Notch signaling, we observed that inhibition of GSK3beta shortened the half-life of Notch1IC. Conversely, activated GSK3beta reduced the quantity of Notch1IC that was degraded by the proteasome. These studies reveal that GSK3beta modulates Notch1 signaling, possibly through direct phosphorylation of the intracellular domain of Notch, and that the activity of GSK3beta protects the intracellular domain from proteasome degradation.
Department of Molecular Pharmacology and Biological Chemistry, Chicago, IL 60611, USA.
Daniel R
DR
Foltz
Michelle C
MC
Santiago
Bridget E
BE
Berechid
Jeffrey S
JS
Nye
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D014157:Transcription Factors
D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3