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Molecular and Cellular Biology, June 2006, p. 4316-4326, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.02183-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Multisite Protein Kinase A and Glycogen Synthase Kinase 3ß Phosphorylation Leads to Gli3 Ubiquitination by SCF^ßTrCP

Département Génétique et Développement, Institut Cochin, INSERM U567, CNRS UMR8104, 24 rue du Faubourg St-Jacques, 75014 Paris, France

Received 10 November 2005/ Returned for modification 22 December 2005/ Accepted 17 March 2006

Gli3 is a zinc finger transcription factor proteolytically processed into a truncated repressor lacking C-terminal activation domains. Gli3 processing is stimulated by protein kinase A (PKA) and inhibited by Hedgehog signaling, a major signaling pathway in vertebrate development and disease. We show here that multisite glycogen synthase kinase 3ß (GSK3ß) phosphorylation and ubiquitination by SCF^ßTrCP are required for Gli3 processing. We identified multiple ßTrCP-binding sites related to the DSGX_2-4S motif in Gli3, which are intertwined with PKA and GSK3ß sites, and SCF^ßTrCP target lysines that are essential for processing. Our results support a simple model whereby PKA triggers a cascade of Gli3 phosphorylation by GSK3ß and CK1 that leads to direct ßTrCP binding and ubiquitination by SCF^ßTrCP. Binding of ßTrCP to Gli3 N- and C-terminal domains lacking DSGX_2-4S-related motifs was also observed, which could reflect indirect interaction via other components of Hedgehog signaling, such as the tumor suppressor Sufu. Gli3 therefore joins a small set of transcription factors whose processing is regulated by the ubiquitin-proteasome pathway. Our study sheds light on the role of PKA phosphorylation in Gli3 processing and will help to analyze how dose-dependent tuning of Gli3 processing is achieved by Hedgehog signaling.

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