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bioRxiv · 10.1101/308841

Regulation of transcription factor SP1 by β-catenin destruction complex modulates Wnt response

Mir, R.·Sharma, A.·Pradhan, S. J.·Galande, S.
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Abstract

The ubiquitous transcription factor Specificity protein 1 (SP1) is heavily modified post-translationally. These modifications are critical for switching its functions and modulation of its transcriptional activity, 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 evidences that SP1 is an integral part of the Wnt signaling pathway. We identified a phosphodegron motif in SP1 that is specific to mammals. In absence of Wnt signaling, GSK3{beta} kinase mediated phosphorylation and {beta}-TrCP E3 ubiquitin ligase mediated ubiquitination is required to induce SP1 degradation. When Wnt signaling is on, SP1 is stabilized in {beta}-catenin-dependent manner. SP1 directly interacts with {beta}-catenin and Wnt signaling induces the stabilization of SP1 by impeding its interaction with {beta}-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 {beta}-catenin and their mutual stabilization is critical for target gene expression, suggesting a feedback mechanism. Upon stabilization SP1 and {beta}-catenin co-occupy the promoters of TCFL2/{beta}-catenin target genes. Collectively, this study uncovers a direct link between SP1 and {beta}-catenin in Wnt signaling pathway.

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Mir, R., Sharma, A., Pradhan, S. J., Galande, S.. 2018-04-26. Regulation of transcription factor SP1 by β-catenin destruction complex modulates Wnt response. https://doi.org/10.1101/308841

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