Regulation of Transcription Factor SP1 by the β-Catenin Destruction Complex Modulates Wnt Response

• Published in: Molecular and cellular biology Vol. 38; no. 22
• Main Authors: Mir, Rafeeq, Sharma, Ankita, Pradhan, Saurabh J., Galande, Sanjeev
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.11.2018; American Society for Microbiology
• Subjects: Amino Acid Sequence; Animals; Axin Signaling Complex - genetics; beta Catenin - genetics; beta-Transducin Repeat-Containing Proteins - genetics; Cell Line; Cell Line, Tumor; destruction complex; Glycogen Synthase Kinase 3 beta - genetics; HCT116 Cells; HEK293 Cells; Humans; phosphodegron; Phosphorylation - genetics; Sequence Alignment; SP1; Sp1 Transcription Factor - genetics; Transcription, Genetic - genetics; Ubiquitin-Protein Ligases - genetics; Ubiquitination - genetics; Wnt signaling; Wnt Signaling Pathway - genetics; β-catenin; destruction complex; β-catenin; Wnt signaling; SP1; phosphodegron
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.00188-18

The ubiquitous transcription factor specificity protein 1 (SP1) is heavily modified posttranslationally. These modifications are critical for switching its functions and modulation of its transcriptional activity and DNA binding and stability. However, the mechanism governing the stability of SP1 by cellular signaling pathways is not well understood. Here, we provide biochemical and functional evidence that SP1 is an integral part of the Wnt signaling pathway. We identified a phosphodegron motif in SP1 that is specific to mammals. In the absence of Wnt signaling, glycogen synthase kinase 3β (GSK3β)-mediated phosphorylation and β-TrCP E3 ubiquitin ligase-mediated ubiquitination are required to induce SP1 degradation. When Wnt signaling is on, SP1 is stabilized in a β-catenin-dependent manner. SP1 directly interacts with β-catenin, and Wnt signaling induces the stabilization of SP1 by impeding its interaction with β-TrCP and axin1, components of the destruction complex. Wnt signaling suppresses ubiquitination and subsequent proteosomal degradation of SP1. Furthermore, SP1 regulates Wnt-dependent stability of β-catenin and their mutual stabilization is critical for target gene expression, suggesting a feedback mechanism. Upon stabilization, SP1 and β-catenin cooccupy the promoters of TCFL2/β-catenin target genes. Collectively, this study uncovers a direct link between SP1 and β-catenin in the Wnt signaling pathway.