Multisite Protein Kinase A and Glycogen Synthase Kinase 3β Phosphorylation Leads to Gli3 Ubiquitination by SCF βTrCP

Author:

Tempé Denis1,Casas Mariana1,Karaz Sonia1,Blanchet-Tournier Marie-Françoise1,Concordet Jean-Paul1

Affiliation:

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

Abstract

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 3β (GSK3β) phosphorylation and ubiquitination by SCF βTrCP are required for Gli3 processing. We identified multiple βTrCP-binding sites related to the DSGX 2 - 4 S motif in Gli3, which are intertwined with PKA and GSK3β sites, and SCF βTrCP target lysines that are essential for processing. Our results support a simple model whereby PKA triggers a cascade of Gli3 phosphorylation by GSK3β and CK1 that leads to direct βTrCP binding and ubiquitination by SCF βTrCP . Binding of βTrCP to Gli3 N- and C-terminal domains lacking DSGX 2 - 4 S-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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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