CaMK IV phosphorylates prohibitin 2 and regulates prohibitin 2-mediated repression of MEF2 transcription

Prohibitin 2 (PHB2) is an evolutionarily conserved and ubiquitously expressed multifunctional protein which is present in various cellular compartments including the nucleus. However, mechanisms underlying various functions of PHB2 are not fully explored yet. Previously we showed that PHB2 interacts with Akt and inhibits muscle differentiation by repressing the transcriptional activity of both MyoD and MEF2. Here we show that Calcium/Calmodulin-dependent kinase IV (CaMK IV) specifically binds to the C terminus of PHB2 and phosphorylates PHB2 at serine 91. Ectopic expression of CaMK IV and PHB2 in C2C12 cells results effectively in decreased PHB2-mediated repression of MEF2-dependent gene expression. Conversely, PHB2 mutant (S91A) resistant to CaMK IV phosphorylation has less effective in relieving the inhibition of MEF2 transcription by PHB2. Our findings suggest that CaMK IV interacts with and regulates PHB2 through phosphorylation, which could be one of the mechanisms underlying the CaMK-mediated activation of MEF2.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (238 K)Download as PowerPoint slideResearch highlights► CaMK IV specifically binds the C terminus of PHB2. ► PHB2 serine 91 serves as the major phosphorylation site for CaMK IV. ► CaMK IV effectively decreased PHB2-mediated repression of MEF2 activity through phosphorylation. ► Serine phosphorylation on PHB2 by CaMK IV relieves its inhibition on MEF2. ► Regulation of PHB2 by CaMK IV may contribute a mechanism underlying the CaMK-mediated activation of MEF2.