Post-Translational Regulations of Transcriptional Activity of RUNX2

Abstract

Runt-related transcription factor 2 (RUNX2) is a key transcription factor for bone formation and osteoblast differentiation. Various signaling pathways and mechanisms that regulate the expression and transcriptional activity of RUNX2 have been thoroughly investigated since the involvement of RUNX2 was first reported in bone formation. As the regulation of Runx2 expression by extracellular signals has recently been reviewed, this review focuses on the regulation of post-translational RUNX2 activity. Transcriptional activity of RUNX2 is regulated at the post-translational level by various enzymes including kinases, acetyl transferases, deacetylases, ubiquitin E3 ligases, and prolyl isomerases. We describe a sequential and linear causality between post-translational modifications of RUNX2 by these enzymes. RUNX2 is one of the most important osteogenic transcription factors; however, it is not a suitable drug target. Here, we suggest enzymes that directly regulate the stability and/or transcriptional activity of RUNX2 at a post-translational level as effective drug targets for treating bone diseases.

Keywords: RUNX2; osteoblast differentiation; phosphorylation-directed Isomerization; post-translational modification; transcriptional activity.

Fig. 1. RUNX2 structure.

The structural and functional domains of mouse RUNX2-II (bone specific isoform) and its post-translational modification sites. Mouse RUNX2-II encodes a 528 amino acid proteins (exons 1-8) with functional domains including a glutamine/alanine-rich domain (QA), a Runt homology domain (RHD), a nuclear localization signal (NLS), a proline/serine/threonine-rich domain (PST), a nuclear matrix targeting signal (NMTS) and a C-terminal VWRPY domain. Red and blue circles over the protein indicate phosphorylation sites that activate and inhibit RUNX2, respectively. Acetylation sites are depicted as purple circles under the protein in the figure. E1-E8 indicate Exon1-Exon8.

Fig. 2. Regulation of RUNX2 stability and transcriptional activity at post-translational levels.

Upon the activation of FGF/FGFR-Erk MAPK signaling pathway, RUNX2 is stabilized and transactivated by multiple post-translational modification cascades: phosphorylation by Erk MAPK, prolyl isomerization by Pin1, acetylation by HAT. Phosphorylation of RUNX2 by GSK3β and cyclin D1/CDK4 induces ubiquitin-proteasomal degradation of RUNX2. BMP/BMPR stimulates p300-mediated RUNX2 acetylation by protecting RUNX2 from Smurf1-mediated degradation.