Background: Gene expression and protein synthesis, mediated by the transcription factor CREB (cAMP response element binding protein), play an important role in learning and memory in several species, including Drosophila, snails, and mice. Patients with the X-linked disorder Coffin-Lowry syndrome (CLS) have cognitive disabilities, distinctive features, and bony abnormalities as well as mutations in RSK2 (ribosomal S6 kinase-2), a protein kinase that activates CREB by phosphorylation at serine 133. In fibroblasts from a single patient with CLS, epidermal growth factor (EGF)-stimulated CREB phosphorylation was reduced.
Methods: The authors assessed endogenous CREB phosphorylation in a CLS fibroblast line by Western blotting and found impaired CREB phosphorylation in response to stimulation by EGF and the protein kinase C (PKC) agonist phorbol 12-myristate 13-acetate (PMA). They studied RSK2 immunoprecipitated from fibroblasts and lymphoblasts from seven patients with CLS and found a wide range in RSK2's capacity to phosphorylate the synthetic CREB-like peptide, CREBtide, after cell stimulation by PMA.
Results: In lymphoblasts from patients with CLS, PMA-stimulated CREBtide phosphorylation was increased 1.2- to 2.7-fold over baseline, compared to an average fourfold increase in controls. Regression analysis suggested a linear relationship between the magnitude of in vitro RSK2-mediated CREBtide phosphorylation and CLS patient intelligence level (p < 0.05).
Conclusions: This report suggests a correlation between human cognitive performance and cellular capacity to activate RSK2. It provides additional evidence that the CREB kinase, RSK2, and CREB phosphorylation may play important roles in human learning and memory, as they do in lower animals.