Serum response factor MADS box serine-162 phosphorylation switches proliferation and myogenic gene programs

Phosphorylation of a cluster of amino acids in the serum response factor (SRIF) "MADS box" alpha l coil DNA binding domain regulated the transcription of genes associated with proliferation or terminal muscle differentiation. Mimicking phosphorylation of serine-162, a target of protein kinase C-a, with an aspartic acid substitution (SRF-S162D) completely inhibited SRF-DNA binding and blocked alpha-actin gene transcription even in the presence of potent myogenic cofactors, while preserving c-fos promoter activity because of stabilization of the ternary complex via Elk-1. Introduction of SRF-S162D into SRF null ES cells permitted transcription of the c-fos gene but was unable to rescue expression of myogenic contractile genes. Transition of proliferating C2C12 myoblasts to postfusion myocytes after serum withdrawal was associated with a progressive decline in SRF-S162 phosphorylation and an increase in alpha-actin gene expression. Hence, the phosphorylation status of serine-162 in the al coil may constitute a novel switch that directs target gene expression into proliferation or differentiation programs.