| Background |
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.Upon mitogenic stimulation, p44/42 ERK1/2 and ERK5 MAP kinases cooperatively phosphorylate p90RSK Thr573 (p90RSK1 numbering) located within the C-terminal kinase domain and Thr359/Ser363 in the linker region between the two kinase domains. Phosphorylation of Thr573 within the activation loop of the p90RSK C-terminal kinase domain promotes activation and directs phosphorylation of Ser380 within the hydrophobic stretch of the linker region. The phosphorylated p90RSK Ser380 acts as a docking site for the constitutively active Ser/Thr kinase PDK1, which in turn phosphorylates Ser221 within the N-terminal kinase domain activation loop, resulting in full enzymatic activation of the p90RSK. Antibodies against these phosphorylation sites are useful for understanding the kinetics and regulation of p90RSK activation.
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