Regulation of Mesenchymal Stem Cell Differentiation by Protein Kinase Signaling Pathways and Transcriptional Modulation

Mesenchymal stem cells are a pluripotent cell type that can differentiate into several distinct lineages. Two key transcription factors, Runx2 and peroxisome proliferator‐activated receptor gamma (PPARγ), drive mesenchymal stem cells to differentiate into either osteoblasts or adipocytes, respectively. How these two transcription factors are regulated in order to specify these alternate cell fates remains a pivotal question. We have found that a 14‐3‐3‐binding protein, TAZ (Transcriptional co‐Activator with PDZ‐binding motif), functions as a molecular rheostat that modulates mesenchymal stem cell differentiation by co‐activating Runx2‐dependent gene transcription while repressing PPARγ‐dependent gene transcription. By modulating TAZ expression in model cell lines, mouse embryonic fibroblasts, and primary mesenchymal stem cells in culture, and in zebrafish in vivo, we observe dramatic alterations in osteogenic versus adipogenic potential. Protein kinases downstream of PI 3‐kinase appear to regulate the activity, molecular interactions, and subcellular localization of TAZ, establishing a signaling pathway linking receptors at the cell surface to nuclear events responsible for cell fate decisions.