Serine phosphorylation of RUNX2 with novel potential functions as negative regulatory mechanisms.
The RUNX family represents a small group of heterodimeric transcription factors that master-regulate osteogenesis and hematopoiesis in mammals. Their genetic defects cause human diseases such as cleidocranial dysplasia (CCD) and acute myelogenous leukemia. However, the mechanism(s) regulating their functions are still poorly understood. Here, we report a novel observation that suggests that the osteogenesis-associated homologue RUNX2 is negatively regulated by the phosphorylation of two conserved serines (S104 and S451) in two distinct functional aspects. The phosphorylation of S104 could abolish the heterodimerization of RUNX2 with the partner subunit, PEBP2beta, which enhances the metabolic stability of RUNX2. On the other hand, the phosphorylation of S451 resides within the C-terminal transcription inhibition domain of RUNX2 and hence is implicated in its functional mobilization. One CCD mutation, S104R of RUNX2, appears to mimic the phosphorylation-dependent inhibition of heterodimerization, thereby rendering RUNX2 metabolically unstable.
Wee
Hee-Jun
HJ
Department of Viral Oncology, Kyoto University, Japan.
Huang
Gang
G
Shigesada
Katsuya
K
Ito
Yoshiaki
Y
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D019281:Dimerization; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins; D010449:Peptide Mapping; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D012694:Serine / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D009363:Neoplasm Proteins; D014157:Transcription Factors; D012694:Serine