Abstract |
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 3beta ( GSK3beta) phosphorylation and ubiquitination by SCFbetaTrCP are required for Gli3 processing. We identified multiple betaTrCP-binding sites related to the DSGX2-4S motif in Gli3, which are intertwined with PKA and GSK3beta sites, and SCFbetaTrCP target lysines that are essential for processing. Our results support a simple model whereby PKA triggers a cascade of Gli3 phosphorylation by GSK3beta and CK1 that leads to direct betaTrCP binding and ubiquitination by SCFbetaTrCP. Binding of betaTrCP 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.
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Authors | Denis Tempé, Mariana Casas, Sonia Karaz, Marie-Françoise Blanchet-Tournier, Jean-Paul Concordet |
Journal | Molecular and cellular biology
(Mol Cell Biol)
Vol. 26
Issue 11
Pg. 4316-26
(Jun 2006)
ISSN: 0270-7306 [Print] United States |
PMID | 16705181
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- GLI3 protein, human
- Kruppel-Like Transcription Factors
- Nerve Tissue Proteins
- Ubiquitin
- Zinc Finger Protein Gli3
- SKP Cullin F-Box Protein Ligases
- GSK3B protein, human
- Glycogen Synthase Kinase 3 beta
- Gsk3b protein, mouse
- Cyclic AMP-Dependent Protein Kinases
- Glycogen Synthase Kinase 3
- Lysine
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Topics |
- Amino Acid Sequence
- Animals
- Binding Sites
(genetics)
- Cells, Cultured
- Cyclic AMP-Dependent Protein Kinases
(chemistry, metabolism)
- Glycogen Synthase Kinase 3
(chemistry, metabolism)
- Glycogen Synthase Kinase 3 beta
- HeLa Cells
- Humans
- Kruppel-Like Transcription Factors
(chemistry, metabolism)
- Lysine
(metabolism)
- Mice
- Molecular Sequence Data
- NIH 3T3 Cells
- Nerve Tissue Proteins
(chemistry, metabolism)
- Phosphorylation
- Protein Binding
- Protein Processing, Post-Translational
- Protein Structure, Tertiary
- SKP Cullin F-Box Protein Ligases
(metabolism)
- Sequence Alignment
- Ubiquitin
(metabolism)
- Zinc Finger Protein Gli3
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