Ribosomal subunit kinase-2 is required for growth factor-stimulated transcription of the c-Fos gene

Ribosomal subunit kinases (Rsk) have been implicated in the regulation of t ranscription by phosphorylating and thereby activating numerous transcripti on factors, such as c-Fos, cAMP responsive element binding protein (CREB), and nuclear receptors, Here we describe the generation and characterization of immortalized embryonic fibroblast cell lines from mice in which the Rsk -2 gene was disrupted by homologous recombinant gene targeting. Rsk-2-defic ient (knockout or KO) cell lines have no detectable Rsk-2 protein, whereas Rsk-1 expression is unaltered as compared with cell lines derived from wild -type control mice. KO cells exhibit a major reduction in platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF)-1-stimulated expr ession of the immediate-early gene c-Fos, This results primarily from a red uced transcriptional activation of the ternary complex factor Elk-l and red uced activation of the serum response factor. The reduced Elk-l activation in KO cells occurs despite normal activation of the mitogen-activated prote in kinase pathway and normal PDGF- and IGF-1-stimulated Elk-1 phosphorylati on. By contrast, PDGF- and IGF-1-stimulated phosphorylation and transcripti onal activation of CREB is unaltered in KO cells. Thus Rsk-2 is required fo r growth factor-stimulated expression of c-Fos and transcriptional activati on of Elk-l and the serum response factor, but not for activation of CREB o r the mitogen-activated protein kinase pathway in response to PDGF and IGF- 1 stimulation.