Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and that contributes to gene activation by histone phosphorylation. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser-28' of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14) (By similarity). ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] Activated by phosphorylation at Ser-350, Thr-571 and Thr-690 by MAP kinases, and by further autophosphorylation of Ser-202, Ser-366 and Ser-371 by the activated C-terminal kinase domain. The active N-terminal kinase domain finally phosphorylates downstream substrates, as well as Ser-740, Ser-742 and Ser-748 in its own C-terminal region (By similarity). Widely expressed with high levels in heart, brain and placenta. Less abundant in lung, kidney and liver. Enzyme activity requires the presence of both kinase domains. Ser-366 and Thr-571 phosphorylation is required for kinase activity. Ser-366 and Ser-202 are autophosphorylated by the C-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain. Phosphorylated at Ser-350, Thr-571 and Thr-690 by MAP kinases. Autophosphorylated at Ser-740, Ser-742 and Ser-748 by the N-terminal kinase domain. Enzyme activity requires the presence of both kinase domains. Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily.