Cdk5/p35 phosphorylates mSds3 and regulates mSds3-mediated repression of transcription

Abstract

Cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase that displays kinase activity predominantly in neurons, is activated by two non-cyclin activators, p35 or p39. Here, we report a physical and functional interaction between the Cdk5/p35 complex and mouse Sds3 (mSdsS), an essential component of mSinS-histone deacetylase (HDAC) co-repressor complex. mSds3 binds to p35 both in vitro and in vivo, enabling active Cdk5 to phosphorylate mSdsS at serine 228. A mSdsS S228A mutant retained mSinS binding activity, but its dimerization was not greatly enhanced by p35 when compared with wild type. Notably, p35 overexpression augmented mSdsS-mediated transcriptional repression in vitro. Interestingly, mutational studies revealed that the ability of exogenous mSds3 to rescue cell growth and viability in mSds3 null cells correlates with its ability to be phosphorylated by Cdk5. The identification of mSdsS as a substrate of the Cdk5/p35 complex reveals a new regulatory mechanism in controlling the mSin3-HDAC transcriptional represser activity and provides a new potential therapeutic means to inhibit specific HDAC activities in disease.