Like the related mitogen- and stress-activated kinases (MSK), all four RSKs contain two catalytic domains, N-terminal (NTKD) and C-terminal (CTKD) kinase domains (13). In inactive RSK, the CTKD binds the autoinhibitory domain (AID) α-helix. When activated, ERK pre-bound to the D-domain phosphorylates RSK residues, including the CTKD activation loop (T570). The CTKD then autophosphorylates S377, permitting PDK1 binding and PDK1 phosphorylation of the NTKD activation loop (S218). The NTKD then phosphorylates RSK substrates.