Rsk1

The p90 ribosomal S6 kinase (Rsk) family comprises four mammalian serine/threonine kinases (Rsk1–4). The first Rsk family member was originally identified as a ~85–92-kDa serine kinase activated during Xenopus laevis oocyte maturation that phosphorylated the 40S ribosomal protein S6 in vitro. Although the p70 S6 kinases 1 and 2 (S6K1 and S6K2) were shown to be the predominant S6 kinases operating in somatic cells, Rsk1 and Rsk2 were recently shown to phosphorylate ribosomal protein S6 in response to Ras/extracellular signal-regulated kinase (ERK) pathway activation. Little is known about specific and overlapping functions of the Rsk isoforms, but the recent identification of specific Rsk inhibitors and the use of RNA interference should help to shed light on the contribution of each Rsk isoform. Mitogenic stimulation of the Ras/ERK pathway leads to the activation of Rsk1. Rsk1 seems to be a multifunctional ERK effector because it participates in various cellular processes, including nuclear signaling. Rsk1 was found to regulate several transcription factors, including SRF, c-Fos, and Nur77. Additional nuclear factors have been shown to be regulated by Rsk1, including MITF, estrogen receptor-α nuclear factor (NF)-ATc4 and ER81. Rsk1 was shown to interact with the transcriptional coactivator CREB-binding protein (CBP), which, interestingly, binds many transcription factors known to be regulated by Rsk1. On the basis of the nature of its substrates, Rsk1 seems to have important functions in cellular growth control and proliferation. Rsk1 may stimulate cell cycle progression through the regulation of immediate early gene products, such as c-Fos, which promotes the expression of cyclin D1 during the G0/G1 transition to S phase. Other proteins through which Rsk1 may stimulate proliferation include the cyclin-dependent kinase (CDK) inhibitor p27^kip1, the Na⁺/H⁺ exchanger NHE-1 and the kinase GSK3. Rsk1 has been shown to phosphorylate and inhibit neuronal NO synthase in response to mitogenic signaling. Rsk1 may also promote proliferation by regulating cell-growth-related protein synthesis.