CDK4 phosphorylates RUNX2

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).<p>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).

在血管内皮细胞中，对高葡萄糖的响应可能通过葡萄糖介导的CCND1（细胞周期蛋白D1）转录上调，激活的CDK4在RUNX2的丝氨酸残基S451（RUNX2-P2异构体由近端P2启动子转录的S451与RUNX2-P1异构体由远端P1启动子转录的S465相匹配）上进行磷酸化。CDK4介导的磷酸化假定发生在RUNX2:CBFB复合体的背景下，因为S451位点的磷酸化不影响RUNX2与CBFB的结合（Wee等人，2002年）。在S451位点上磷酸化的RUNX2显示出与靶启动子，特别是CDKN1A（p21）增强的结合，这增强了RUNX2介导的CDKN1A转录的抑制（Pierce等人，2012年）。RUNX2在S451位点的磷酸化还增强了RUNX2:CBFB复合体与骨钙蛋白基因启动子的结合（Wee等人，2002年）。据报道，CDK4:CCND1复合体通过CDK4对RUNX2-P1丝氨酸位点S465（与小鼠Runx2-P1丝氨酸残基S472相对应）的磷酸化将RUNX2靶向泛素化并介导蛋白质降解，但负责的泛素连接酶尚未确定（Shen等人，2006年）。BMP2信号通路据报道干扰了CDK4诱导的RUNX2蛋白质降解（Shu等人，2011年）。甲状旁腺激素相关蛋白（PTHLH，也称为PTHrP）涉及正调控CCND1介导的RUNX2降解（Zhang等人，2009年）。