Regulation of the osteoblast‐specific transcription factor, Runx2: Responsiveness to multiple signal transduction pathways

Abstract

The Cbfa1/Runx2 is an important transcription factor necessary for osteoblast differentiation and bone formation. However, the signaling pathways regulating Runx2 activity are just beginning to be understood. Inconsistencies between Runx2 mRNA or protein levels and its transcriptional activity suggests that posttranslational modification and/or protein-protein interactions may regulate this factor. Runx2 can be phosphorylated and activated by the mitogen-activated protein kinase (MAPK) pathway. This pathway can be stimulated by a variety of signals including those initiated by extracellular matrix (ECM), osteogenic growth factors like bone morphogenic proteins (BMPs) and fibroblast growth factor-2 (FGF-2), mechanical loading and hormones such as parathyroid hormone (PTH). Protein kinase A (PKA) may also phosphorylate/activate Runx2 under certain conditions. In addition, Runx2 activity is enhanced by protein-protein interactions as are seen with PTH-induced Runx2/AP-1 and BMP-mediated Runx2/Smads interactions. Mechanisms for interaction with Runx2 are complex including binding of distinct components such as AP-1 factors and Smads proteins to separate DNA regions in target gene promoters and direct physical interactions between Runx2 and AP-1/Smad factors. Post-translational modifications such as phosphorylation may influence interactions between Runx2 and other nuclear factors. These findings suggest that Runx2 plays a central role in coordinating multiple signals involved in osteoblast differentiation.

Retinoid-suppressed phosphorylation of RARα mediates the differentiation pathway of osteosarcoma cells

“…Previous studies have shown that FGF (Ornitz and Marie, 2002), BMP (Chen et al, 2004) and WNT pathways (Liu et al, 2008) are important signaling networks coexisting within bone cells during development and carcinogenesis. The FGF-PI3K-AKT signaling pathway and the canonical WNT signaling pathway cross talk at glycogen synthase kinase-b during carcinogenesis (Katoh, 2006), whereas FGF and BMP share MAPKdependent pathways in regulating osteogenesis (Franceschi and Xiao, 2003). We find that upon osteoblastic differentiation induced by RA-RARa-FGF8f, several important MAPK, BMP and WNT signaling pathways are simultaneously activated ( Figure 5).…”

Runx2 is essential for larval hyobranchial cartilage formation in Xenopus laevis

“…any of several levels of regulation, including splice variation, ubiquitination, acetylation, and phosphorylation, as well as functional control through various DNA binding partners and inhibitors (reviewed in Franceschi and Xiao, 2003;Iwamoto et al, 2003;Bae and Lee, 2005;Lengner et al, 2005;Goldring et al, 2006).…”

“…However, neither species requires the gene product to be functional during early cartilage formation. Runx2Јs inactivity during amniote cartilage formation may be attributed to several different levels of regulation imposed on the gene product (Franceschi and Xiao, 2003;Xiao et al, 2003;Wang et al, 2004;Bae and Lee, 2005;Lengner et al, 2005;Goldring et al, 2006). A change in post-transcriptional modification of Runx2 or in the function of one of its co-factors may account for the possible evolutionary loss of the transcript's function during cartilage formation within the amniote lineage.…”

A role for Runx2 in normal mammary gland and breast cancer bone metastasis

“…It will therefore be important to determine whether Runx2 expression is actually increased in breast cancers, as there is still uncertainty as to whether Runx2 expression is up-regulated in metastatic cells compared to non-metastatic cells. Indeed, Runx2 is the target of a number of signal transduction pathways, some of which are known to be aberrantly activated in cancer cells [reviewed in Franceschi and Xiao, 2003;Campbell and Der, 2004]. In metastatic cells constitutive activation of signaling pathways may in turn lead to activation of Runx2, and thus increased expression of its target genes (Fig.…”