Multiple protein arginine methyltransferases are involved in transcriptional 
activation of nuclear receptors. Coactivator-associated arginine 
methyltransferase 1 (CARM1)-mediated histone methylation has been shown to 
activate nuclear receptor-dependent transcription; however, little is known 
about the regulation of its enzymatic activity. Here, we report that the 
methyltransferase activity of CARM1 is negatively regulated through 
phosphorylation at a conserved serine residue. When the serine residue is 
mutated to glutamic acid, which mimics the phosphorylated serine residue, the 
mutant CARM1 exhibits diminished ability to bind the methyl donor 
adenosylmethionine and diminished histone methylation activity. Moreover, such 
mutation leads to the inhibition of CARM1 transactivation of estrogen 
receptor-dependent transcription. Our results provide an example for the 
regulation of protein arginine methyltransferase activity by phosphorylation. As 
CARM1 is a potent transcriptional coactivator of estrogen receptor, our results 
suggest that phosphorylation of CARM1 serves as a unique mechanism for 
inactivating CARM1-regulated estrogen-dependent gene expression.