The mechanism of CREB activation via Ser271 phosphorylation remains uncharacterized. Arsenic stabilizes HIPK2 and HIPK1 and induces the phosphorylation of CREB at Ser271. Phosphorylation of CREB at Ser271 enhances the transcription of CREB target genes. Phosphorylation of CREB at Ser271 facilitates interaction with TAF4. The HIPK2-Ser271CREB-TAF4 axis signals in parallel with the PKA-Ser133CREB-CBP axis.