Cytoplasmic to nuclear signal transduction by mitogen-activated protein kinase and 90 kDa ribosomal S6 kinase.

The binding of growth factors to their cognate receptors at the plasma membrane elicits a variety of biochemical and genomic changes that lead ultimately to cell proliferation or to differentiation. One of the cellular responses is the transcriptional activation of immediate-early genes. While much attention has focused on the identification and characterization of these genes, the mechanisms linking receptor occupancy to their rapid and transient expression remain largely unknown. The identification of some of these transcription factors as phosphoproteins has implied the involvement of protein phosphorylation in transcriptional regulation [ 11. However, the nature of the growth-responsive kinases that participate in this process has not yet been elucidated. Several protein serinelthreonine kinases that participate in regulating cell growth and development have been identified recently. Among these are two distinct families of 40 S ribosomal protein S6 kinases, pp9OrSk (RSK, 90 kDa-ribosomal S6 kinase) and pp7OShk (70 kDa-ribosomal S6 kinase) [2, 31. These protein serine/threonine kinases are differentially regulated by a variety of mitogens via distinct signalling cascades [4, 51. Both enzymes are regulated by serinelthreonine phosphorylation, suggesting that protein serinelthreonine kinases exist upstream in the signalling pathways that regulate these enzymes. While the putative ~ ~ 7 0 " ~ ~ protein kinase has not yet been identified, several studies have provided evidence that pp9OrSk is phosphorylated and activated by mitogen-activated protein kinases (MAP kinases) [6, 71. MAP k' inases have been shown to be activated by phosphorylation both at threonine and at tyrosine residues in many types of cells in response to various extracellular stimuli [8]. In this paper, we demonstrate that MAP kinases and RSK are localized in the nucleus as well as in the cytoplasm of cultured cells. The activated enzymes can phosphorylate several nuclear