Alternative titles; symbols
HGNC Approved Gene Symbol: RPS6KA1
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38): 1:26,529,761-26,575,025 (from NCBI)
The RSK (ribosomal S6 kinase) family comprises growth factor-regulated serine/threonine kinases, known also as p90(rsk). Homologs of RSK exist in several species. The highly conserved feature of all members of the RSK family is the presence of 2 nonidentical kinase catalytic domains. RSKs are implicated in the activation of the mitogen-activated kinase (MAPK) cascade (see 176872) and the stimulation of cell proliferation (at the transition between phases G0 and G1 of the cell cycle) and differentiation.
Moller et al. (1994) described the cloning and characterization of 3 genes encoding RSKs, which they called HU1 (RPS6KA1), HU2 (RPS6KA2; 601685), and HU3 (RPS6KA3; 300075). The HU1 cDNA (GenBank L07597) encodes a predicted 735-amino acid protein containing 2 distinct consensus ATP-binding site sequences. Northern blot and RNase protection analyses detected an approximately 3.5-kb HU1 transcript in lymphocytes, skeletal muscle, liver, and adipose tissue.
Zeniou et al. (2002) determined the expression of the RSK1, RSK2 (300075), and RSK3 (601685) genes in various human tissues, during mouse embryogenesis, and in mouse brain. The 3 RSK mRNAs were expressed in all human tissues and brain regions tested, supporting functional redundancy. However, tissue-specific variations in levels suggested that the proteins may also serve specific roles. The mouse Rsk3 gene was prominently expressed in the developing neural and sensory tissues, whereas Rsk1 gene expression was the strongest in various other tissues with high proliferative activity, suggesting distinct roles during development. In adult mouse brain, the highest levels of Rsk2 expression were observed in regions with high synaptic activity, including the neocortex, the hippocampus, and Purkinje cells. The authors suggested that in these areas, which are essential to cognitive function and learning, the RSK1 and RSK3 genes may not be able to fully compensate for a lack of RSK2 function.
Bonni et al. (1999) characterized the mechanism by which the RAS (see 190020)-MAPK signaling pathway (see 602448) mediates growth factor-dependent cell survival. The MAP-activated kinases, the Rsks, catalyzed the phosphorylation of the proapoptotic protein BAD (603167) at ser112 both in vitro and in vivo. The Rsk-induced phosphorylation of BAD at ser112 suppressed BAD-mediated apoptosis in neurons. The Rsks are known to phosphorylate the transcription factor CREB (see 123810) at ser133. Activated CREB promoted cell survival, and inhibition of CREB phosphorylation at ser133 triggered apoptosis. Bonni et al. (1999) suggested that the MAP kinase signaling pathway promotes cell survival by a dual mechanism comprising the posttranslational modification and inactivation of a component of the cell death machinery and the increased transcription of prosurvival genes.
Bhatt and Ferrell (1999) demonstrated that Xenopus laevis egg extracts immunodepleted of Rsk lost their capacity to undergo mitotic arrest in response to activation of the Mos (190060)-MEK1 (176872)-p42 (603441) MAPK cascade of protein kinases. Replenishing Rsk-depleted extracts with catalytically competent Rsk protein restored the ability of the extracts to undergo mitotic arrest. Bhatt and Ferrell (1999) concluded that Rsk appears to be essential for cytostatic factor arrest.
Gross et al. (1999) investigated whether cytostatic factor arrest is mediated by the protein kinase p90 Rsk, which is phosphorylated and activated by MAPK, by expressing a constitutively activated form of Rsk in Xenopus embryos. Expression of constitutively active Rsk resulted in cleavage arrest, and cytologic analysis showed that arrested blastomeres were in M phase with prominent spindles characteristic of meiotic metaphase. Thus, Gross et al. (1999) concluded that Rsk appears to be the mediator of MAPK-dependent cytostatic factor arrest in vertebrate unfertilized eggs. Gross et al. (1999) found that because Rsk expression did not activate the endogenous MAPK pathway, MAPK required no other substrate for induction of cytostatic factor arrest. They also stated that cytostatic factor arrest is not a consequence of direct regulation of the spindle assembly checkpoint or the anaphase-promoting complex by MAPK.
Cohen et al. (2005) used a structural bioinformatics approach to identify 2 selectivity filters, a threonine and a cysteine, at defined positions in the active site of p90 ribosomal protein S6 kinase (RSK). A fluoromethylketone inhibitor, designed to exploit both selectivity filters, potently and selectively inactivated RSK1 and RSK2 in mammalian cells. Kinases with only one selectivity filter were resistant to the inhibitor, yet they became sensitized after genetic introduction of the second selectivity filter. Thus, Cohen et al. (2005) concluded that 2 amino acids that distinguish RSK from other protein kinases are sufficient to confer inhibitor sensitivity.
Nishiyama et al. (2007) reported that in Xenopus eggs Erp1 (see 609110) is a substrate of p90rsk, and that Mos (a mitogen-activated protein kinase (MAPK) kinase kinase)-dependent phosphorylation of Erp1 by p90rsk at thr336, ser342, and ser344 is crucial for both stabilizing Erp1 and establishing cytostatic factor (CSF) arrest in meiosis II oocytes. Semiquantitative analysis of CSF-arrested egg extracts revealed that the Mos-dependent phosphorylation of Erp1 enhances, but does not generate, the activity of Erp1 that maintains metaphase arrest. Nishiyama et al. (2007) concluded that their results also suggested that Erp1 inhibits cyclin B (see 123836) degradation by binding the anaphase-promoting complex/cyclosome (APC/C) at its carboxy-terminal destruction box, and this binding is also enhanced by the Mos-dependent phosphorylation. Thus, Mos and Erp1 collaboratively establish and maintain metaphase II arrest in Xenopus eggs.
Inoue et al. (2007) demonstrated that p90rsk, the kinase immediately downstream from Mos-MAPK, directly targets Erp1 for CSF arrest in Xenopus oocytes. Erp1 is synthesized immediately after meiosis I, and the Mos-MAPK pathway or p90rsk is essential for CSF arrest by Erp1. p90rsk can directly phosphorylate Erp1 on ser335/thr336 both in vivo and in vitro, and upregulates both Erp1 stability and activity. Erp1 is also present in early embryos, but has little CSF activity owing, at least in part, to the absence of p90rsk activity. Inoue et al. (2007) concluded that their results clarified the direct link of the classical Mos-MAPK pathway to Erp1 in meiotic arrest of vertebrate oocytes.
By analysis of somatic cell hybrids, Moller et al. (1994) mapped the RPS6KA1 gene to chromosome 3.
Bhatt, R. R., Ferrell, J. E., Jr. The protein kinase p90 Rsk as an essential mediator of cytostatic factor activity. Science 286: 1362-1365, 1999. [PubMed: 10558991] [Full Text: https://doi.org/10.1126/science.286.5443.1362]
Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu, M. A., Greenberg, M. E. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286: 1358-1362, 1999. [PubMed: 10558990] [Full Text: https://doi.org/10.1126/science.286.5443.1358]
Cohen, M. S., Zhang, C., Shokat, K. M., Taunton, J. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science 308: 1318-1321, 2005. [PubMed: 15919995] [Full Text: https://doi.org/10.1126/science1108367]
Gross, S. D., Schwab, M. S., Lewellyn, A. L., Maller, J. L. Induction of metaphase arrest in cleaving Xenopus embryos by the protein kinase p90(Rsk). Science 286: 1365-1367, 1999. [PubMed: 10558992] [Full Text: https://doi.org/10.1126/science.286.5443.1365]
Inoue, D., Ohe, M., Kanemori, Y., Nobui, T., Sagata, N. A direct link of the Mos-MAPK pathway to Erp1/Emi2 in meiotic arrest of Xenopus laevis eggs. Nature 446: 1100-1104, 2007. [PubMed: 17410130] [Full Text: https://doi.org/10.1038/nature05688]
Moller, D. E., Xia, C. H., Tang, W., Zhu, A. X., Jakubowski, M. Human rsk isoforms: cloning and characterization of tissue-specific expression. Am. J. Physiol. 266: C351-C359, 1994. [PubMed: 8141249] [Full Text: https://doi.org/10.1152/ajpcell.1994.266.2.C351]
Nishiyama, T., Ohsumi, K., Kishimoto, T. Phosphorylation of Erp1 by p90rsk is required for cytostatic factor arrest in Xenopus laevis eggs. Nature 446: 1096-1099, 2007. [PubMed: 17410129] [Full Text: https://doi.org/10.1038/nature05696]
Zeniou, M., Ding, T., Trivier, E., Hanauer, A. Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning. Hum. Molec. Genet. 11: 2929-2940, 2002. [PubMed: 12393804] [Full Text: https://doi.org/10.1093/hmg/11.23.2929]