Although our work does not rule out some extent of substrate specificity, it suggests that the substrate ranges of different RSK isoform largely overlap and that the differences observed between physiological activities of the four RSK isoforms, such as RSK2-specific mutations in the Coffin-Lowry syndrome (16), may be more related to the different expression levels of these isoforms in different cell types. This evidence concerns the gene RPS6KA1 and Coffin-Lowry syndrome.