The 90 kDa ribosomal S6 kinases (RSK1-4) are a family of widely expressed Ser/Thr kinases characterized by two nonidentical, functional kinase domains and a carboxy-terminal docking site for extracellular signal-regulated kinases (ERKs) . Several sites both within and outside of the RSK kinase domain, including Ser380, Thr359, Ser363, and Thr573, are important for kinase activation. RSK1-3 are activated via coordinated phosphorylation by MAPKs, autophosphorylation, and phosphoinositide-3-OH kinase (PI3K) in response to many growth factors, polypeptide hormones, and neurotransmitters.

Stimulation by various growth factors leads to activation of RSK2, which is a critical downstream effector kinase in several pathways. EGF stimulation leads to phosphorylation of CREB at Ser133 and phosphorylation of histone H3 in vivo by RSK2. RSK2 phosphorylation of p53 may help regulate chromatin structure and cell cycle . RSK2 is prominently expressed in the brain and is essential for cognitive function and learning. During development, RSK2 regulates the differentiation of osteoblasts and skeletal muscle cells. Mutations in the corresponding gene are associated with Coffin-Lowry syndrome (CLS), an X-linked disorder characterized by mental retardation and the presence of characteristic facial anomalies.