RSK-2 ACTIVITY IS NECESSARY FOR EPIDERMAL GROWTH FACTOR-INDUCED PHOSPHORYLATION OF CREB PROTEIN AND TRANSCRIPTION OF C-FOS GENE

Activation by growth factors of the Ras-dependent signaling cascade re sults in the induction of p90 ribosomal S6 kinases (p90(rsk)). These a re translocated into the nucleus upon phosphorylation by mitogen-activ ated protein kinases, with which p90(rsk) are physically associated in the cytoplasm, In humans there are three isoforms of the p90(rsk) fam ily, Rsk-1, Rsk-2, and Rsk3, which are products of distinct genes. Alt hough these isoforms are structurally very similar, little is known ab out their functional specificity. Recently, mutations in the Rsk-3 gen e have been associated with the Coffin-Lowry syndrome (CLS). We have s tudied a fibroblast cell line established from a CLS patient that bear s a nonfunctional Rsk-2, Here,ve document that in CLS fibroblasts ther e is a drastic attenuation in the induced Ser-133 phosphorylation of t ranscription factor CREB (cAMP response element-binding protein) in re sponse to epidermal growth factor stimulation. The effect is specific, since response to serum, cAMP, and UV light is unaltered. Furthermore , epidermal growth factor-induced expression of c-fos is severely impa ired in CLS fibroblasts despite normal phosphorylation of serum respon se factor and Elk-1, Finally, coexpression of Rsk-2 in transfected cel ls results in the activation of the c-fos promoter via the cAMP-respon sive element. Thus, we establish a link in the transduction of a speci fic growth factor signal to changes in gene expression via the phospho rylation of CREB by Rsk-2.