In endothelial cells, in response to high glucose, probably via glucose-mediated upregulation of CCND1 (cyclin D1) transcription, activated CDK4 phosphorylates RUNX2 on serine residue S451 (S451 in RUNX2-P2 isoform transcribed from the proximal P2 promoter matches S465 in RUNX2-P1 isoform transcribed from the distal P1 promoter). CDK4-mediated phosphorylation is assumed to happen in the context of the RUNX2:CBFB complex, as phosphorylation at S451 does not affect RUNX2 binding to CBFB (Wee et al. 2002). RUNX2 phosphorylated at S451 shows increased binding to target promoters, CDKN1A (p21) in particular, which enhances RUNX2-mediated repression of CDKN1A transcription (Pierce et al. 2012). Phosphorylation of RUNX2 at S451 also enhances binding of the RUNX2:CBFB complex to the osteocalcin gene promoter (Wee et al. 2002).
Phosphorylation of RUNX2-P1 serine site S465 (corresponds to mouse Runx2-P1 serine residue S472) by the CDK4:CCND1 complex has been reported to target RUNX2 for ubiquitination and proteasome-mediated degradation, but the responsible ubiquitin ligase has not been identified (Shen et al. 2006). BMP2 signaling was reported to interfere with CDK4-induced RUNX2 protein degradation (Shu et al. 2011). Parathyroid hormone-related protein (PTHLH, also known as PTHrP) is implicated in positive regulation of CCND1-mediated degradation of RUNX2 (Zhang et al. 2009).