Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c- fos gene

Abstract

Activation by growth factors of the Rasdependent signaling cascade results in the induction of p90 ribosomal S6 kinases (p90 rsk ). These are translocated into the nucleus upon phosphorylation by mitogen-activated protein kinases, with which p90 rsk are physically associated in the cytoplasm. In humans there are three isoforms of the p90 rsk family, Rsk-1, Rsk-2, and Rsk-3, which are products of distinct genes. Although these isoforms are structurally very similar, little is known about their functional specificity. Recently, mutations in the Rsk-2 gene have been associated with the Coffin-Lowry syndrome (CLS). We have studied a fibroblast cell line established from a CLS patient that bears a nonfunctional Rsk-2. Here we document that in CLS fibroblasts there is a drastic attenuation in the induced Ser-133 phosphorylation of transcription factor CREB (cAMP response element-binding protein) in response 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 impaired in CLS fibroblasts despite normal phosphorylation of serum response factor and Elk-1. Finally, coexpression of Rsk-2 in transfected cells results in the activation of the c-fos promoter via the cAMP-responsive element. Thus, we establish a link in the transduction of a specific growth factor signal to changes in gene expression via the phosphorylation of CREB by Rsk-2.

Activation of the c-fos enhancer by the Erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites

“…Mutations in the RSK2 gene and loss of RSK2 activity have also been associated with Co n-Lowry syndrome (CLS) which is characterized by severe psychomotor retardation, facial and digital dymorphisms, and progressive skeletal deformations (Trivier et al, 1996;Young, 1988). EGF-induced CREB phosphorylation was lost in ®broblasts from CLS patients while there was no change in cAMP, UV or serum induced CREB phosphorylation (De Cesare et al, 1998). EGFinduction of c-fos expression was also greatly reduced in CLS cells suggesting that RSK2 is required for EGF induction of c-fos, possibly through phosphorylation of CREB and ATF1.…”

“…The role of RSK2 in c-fos regulation was particularly highlighted in ®broblasts from Co n-Lowry syndrome (CLS) patients that have a defect in the RSK2 gene. In these cells EGF induction of c-fos as well as EGF-induced phosphorylation of CREB were severely impaired (De Cesare et al, 1998). In contrast, serum induction of c-fos and CREB phosphorylation were unaltered in CLS cells, suggesting that di erent signaling pathways are utilized.…”

Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway

“…In 1996, Xing et al found that introduction of activated ras oncogene into PC12 cells regulated gene expression by activating RAF and MAP kinase and then RSK2 of pp90RSK family to phosphorylate CREB (Xing et al, 1996;Cesare et al, 1998;Beaupre et al, 1999). The CREB was the earliest found to regulate gene expression when the level of cAMP increases (Bonni et al, 1995).…”

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

“…MAP kinases have been demonstrated to phosphorylate Elk-1, leading to enhanced formation of the ternary complex and induction of c-fos Gille et al, 1995). Furthermore, it has recently been shown that MAP kinase dependent activation of the serine/threonine kinase Rsk-2 can mediate c-fos induction (De Cesare et al, 1998). Phosphorylation of Shc at Tyr317 has been demonstrated to mediate Ras/MAP kinase activation and cfos induction.…”