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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 SCFßTrCP

Denis Tempé, Mariana Casas, Sonia Karaz, Marie-Françoise Blanchet-Tournier, and Jean-Paul Concordet*

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 SCFßTrCP are required for Gli3 processing. We identified multiple ßTrCP-binding sites related to the DSGX2-4S motif in Gli3, which are intertwined with PKA and GSK3ß sites, and SCFßTrCP 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 SCFßTrCP. Binding of ßTrCP to Gli3 N- and C-terminal domains lacking DSGX2-4S-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.

* Corresponding author. Mailing address: Département Génétique et Développement, Institut Cochin, 24 rue du Faubourg St-Jacques, 75014 Paris, France. Phone: (33) 1 44412436. Fax: (33) 1 44412421. E-mail: concordet{at}cochin.inserm.fr.

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.



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