Genomes and Genes
90 kda ribosomal protein s6 kinases
Summary: A family of ribosomal protein S6 kinases that are structurally distinguished from RIBOSOMAL PROTEIN S6 KINASES, 70-KDA by their apparent molecular size and the fact they contain two functional kinase domains. Although considered RIBOSOMAL PROTEIN S6 KINASES, members of this family are activated via the MAP KINASE SIGNALING SYSTEM and have been shown to act on a diverse array of substrates that are involved in cellular regulation such as RIBOSOMAL PROTEIN S6 and CAMP RESPONSE ELEMENT-BINDING PROTEIN.
- Dummler B, Hauge C, Silber J, Yntema H, Kruse L, Kofoed B, et al. Functional characterization of human RSK4, a new 90-kDa ribosomal S6 kinase, reveals constitutive activation in most cell types. J Biol Chem. 2005;280:13304-14 pubmed
- Kang S, Dong S, Gu T, Guo A, Cohen M, Lonial S, et al. FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway. Cancer Cell. 2007;12:201-14 pubmed..Our findings suggest that FGFR3 mediates hematopoietic transformation by activating RSK2 in a two-step fashion, promoting both the ERK-RSK2 interaction and subsequent phosphorylation of RSK2 by ERK. ..
- Chwang W, Arthur J, Schumacher A, Sweatt J. The nuclear kinase mitogen- and stress-activated protein kinase 1 regulates hippocampal chromatin remodeling in memory formation. J Neurosci. 2007;27:12732-42 pubmed..This suggests that CREB phosphorylation and histone acetylation represent parallel targets of MSK1 function. Our study identifies MSK1 as an important regulator of chromatin remodeling in long-term memory...
- Cohen M, Zhang C, Shokat K, Taunton J. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science. 2005;308:1318-21 pubmed..Thus, two amino acids that distinguish RSK from other protein kinases are sufficient to confer inhibitor sensitivity. ..
- Kimball S, Siegfried B, Jefferson L. Glucagon represses signaling through the mammalian target of rapamycin in rat liver by activating AMP-activated protein kinase. J Biol Chem. 2004;279:54103-9 pubmed..Amino acids also enhance AMPK phosphorylation, although to a lesser extent than glucagon and amino acids combined. ..
- Pi X, Yan C, Berk B. Big mitogen-activated protein kinase (BMK1)/ERK5 protects endothelial cells from apoptosis. Circ Res. 2004;94:362-9 pubmed..These results suggest that BMK1 activation by steady laminar flow is atheroprotective by inhibiting EC apoptosis via phosphorylation of Bad. ..
- Soloaga A, Thomson S, Wiggin G, Rampersaud N, Dyson M, Hazzalin C, et al. MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14. EMBO J. 2003;22:2788-97 pubmed..We conclude that MSKs are the major kinases for histone H3 and HMG-14 in response to mitogenic and stress stimuli in fibroblasts. ..
- Malakhova M, Tereshko V, Lee S, Yao K, Cho Y, Bode A, et al. Structural basis for activation of the autoinhibitory C-terminal kinase domain of p90 RSK2. Nat Struct Mol Biol. 2008;15:112-3 pubmed..We suggest a mechanism of activation through displacement of the alphaL-helix and rearrangement of the conserved residue Glu500, as well as the reorganization of the T-loop into the active conformation. ..
- Holz M, Ballif B, Gygi S, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005;123:569-80 pubmed..Thus, the eIF3 preinitiation complex acts as a scaffold to coordinate a dynamic sequence of events in response to stimuli that promote efficient protein synthesis. ..
- Ranganathan A, Pearson G, Chrestensen C, Sturgill T, Cobb M. The MAP kinase ERK5 binds to and phosphorylates p90 RSK. Arch Biochem Biophys. 2006;449:8-16 pubmed..The large C-terminal domain of ERK5 is not required for binding or activation of RSK by ERK5; however, the common docking or CD domain of ERK5 and the docking or D domain of RSK are important for their association. ..
- Arthur J. MSK activation and physiological roles. Front Biosci. 2008;13:5866-79 pubmed..The physiological roles of MSKs still remain to be completely determined, however recent work has suggested a role for MSKs in neuronal synaptic plasticity and in regulating cytokine production in the innate immune system. ..
- Park I, Erbay E, Nuzzi P, Chen J. Skeletal myocyte hypertrophy requires mTOR kinase activity and S6K1. Exp Cell Res. 2005;309:211-9 pubmed
- Shahbazian D, Roux P, Mieulet V, Cohen M, Raught B, Taunton J, et al. The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO J. 2006;25:2781-91 pubmed..Phosphorylation of eIF4B on Ser422 by RSK and S6K is physiologically significant, as it increases the interaction of eIF4B with the eukaryotic translation initiation factor 3. ..
- Bignone P, Lee K, Liu Y, Emilion G, Finch J, Soosay A, et al. RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer. Oncogene. 2007;26:683-700 pubmed..In contrast, small interfering RNA against RPS6KA2 showed the opposite effect in 41M cells. The above results suggest that RPS6KA2 is a putative tumour suppressor gene to explain allele loss at 6q27. ..
- Vicent G, Ballaré C, Nacht A, Clausell J, Subtil Rodríguez A, Quiles I, et al. Induction of progesterone target genes requires activation of Erk and Msk kinases and phosphorylation of histone H3. Mol Cell. 2006;24:367-81 pubmed..Inhibition of Msk1 activation blocks recruitment of the kinase complex, H3 phosphorylation, and HP1gamma displacement, thus precluding remodeling and induction of the promoter. ..
- Silverman E, Frodin M, Gammeltoft S, Maller J. Activation of p90 Rsk1 is sufficient for differentiation of PC12 cells. Mol Cell Biol. 2004;24:10573-83 pubmed..Collectively, our data demonstrate a key role for Rsk1 in the differentiation process of PC12 cells. ..
- Roze E, Betuing S, Deyts C, Marcon E, Brami Cherrier K, Pages C, et al. Mitogen- and stress-activated protein kinase-1 deficiency is involved in expanded-huntingtin-induced transcriptional dysregulation and striatal death. FASEB J. 2008;22:1083-93 pubmed..We propose that MSK-1 deficiency is involved in transcriptional dysregulation and striatal degeneration. Restoration of its expression and activity may be a new therapeutic target in HD. ..
- Roux P, Ballif B, Anjum R, Gygi S, Blenis J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci U S A. 2004;101:13489-94 pubmed..Together, our data unveil a regulatory mechanism by which the Ras/MAPK and PI3K pathways converge on the tumor suppressor tuberin to inhibit its function. ..
- Pende M, Um S, Mieulet V, Sticker M, Goss V, Mestan J, et al. S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol. 2004;24:3112-24 pubmed..These data reveal a redundancy between the S6K and the MAPK pathways in mediating early S6 phosphorylation in response to mitogens. ..
- Cho Y, Yao K, Bode A, Bergen H, Madden B, Oh S, et al. RSK2 mediates muscle cell differentiation through regulation of NFAT3. J Biol Chem. 2007;282:8380-92 pubmed..Multinucleated myotube differentiation was inhibited by small interfering RNA against RSK2, ERK1/2, or NFAT3. These results demonstrate that RSK2 is an important kinase for NFAT3 in mediating myotube differentiation. ..
- Paronetto M, Giorda E, Carsetti R, Rossi P, Geremia R, Sette C. Functional interaction between p90Rsk2 and Emi1 contributes to the metaphase arrest of mouse oocytes. EMBO J. 2004;23:4649-59 pubmed
- Hauge C, Frodin M. RSK and MSK in MAP kinase signalling. J Cell Sci. 2006;119:3021-3 pubmed
- Soulet F, Bailly K, Roga S, Lavigne A, Amalric F, Bouche G. Exogenously added fibroblast growth factor 2 (FGF-2) to NIH3T3 cells interacts with nuclear ribosomal S6 kinase 2 (RSK2) in a cell cycle-dependent manner. J Biol Chem. 2005;280:25604-10 pubmed..FGF-2 mutants (FGF-2 S117A, FGF-2 L127A, and FGF-2 K128A) that fail to interact in vitro with RSK2 fail to maintain a sustained RSK2 activity in vivo. ..
- Cuadrado A, Nebreda A. New insights into RSK activation and hematopoietic cancer. Cancer Cell. 2007;12:187-9 pubmed..Constitutively active FGFR3 directly phosphorylates RSK2 on Tyr529, which primes RSK2 for activation by the kinases ERK1 and ERK2 (ERK1/2). In turn, RSK2 activity plays an important role in the survival of FGFR3-expressing MM cells. ..
- Anjum R, Blenis J. The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol. 2008;9:747-58 pubmed publisher..Collectively, these data expand the current models of RSK signalling and highlight potential directions of research in RSK-mediated survival, growth, proliferation and migration. ..
- Beck I, Vanden Berghe W, Vermeulen L, Bougarne N, Vander Cruyssen B, Haegeman G, et al. Altered subcellular distribution of MSK1 induced by glucocorticoids contributes to NF-kappaB inhibition. EMBO J. 2008;27:1682-93 pubmed publisher..These findings unveil a novel aspect within the GR-mediated NF-kappaB-targeting anti-inflammatory mechanism. ..
- Davie J. MSK1 and MSK2 mediate mitogen- and stress-induced phosphorylation of histone H3: a controversy resolved. Sci STKE. 2003;2003:PE33 pubmed
- Duncan E, Anest V, Cogswell P, Baldwin A. The kinases MSK1 and MSK2 are required for epidermal growth factor-induced, but not tumor necrosis factor-induced, histone H3 Ser10 phosphorylation. J Biol Chem. 2006;281:12521-5 pubmed..These studies demonstrate the existence of pathway-specific mechanisms to control histone H3-Ser10 phosphorylation and gene expression. ..
- Hancock C, Macias A, Lee E, Yu S, MacKerell A, Shapiro P. Identification of novel extracellular signal-regulated kinase docking domain inhibitors. J Med Chem. 2005;48:4586-95 pubmed..These active compounds may serve as lead candidates for development of novel specific inhibitors of ERK-substrate interactions involved in cell proliferation. ..
- Clark D, Errington T, Smith J, Frierson H, Weber M, Lannigan D. The serine/threonine protein kinase, p90 ribosomal S6 kinase, is an important regulator of prostate cancer cell proliferation. Cancer Res. 2005;65:3108-16 pubmed..These results suggest that proliferation of some prostate cancer cells is dependent on RSK activity and support the hypothesis that RSK may be an important chemotherapeutic target for prostate cancer. ..
- Smith J, Poteet Smith C, Xu Y, Errington T, Hecht S, Lannigan D. Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation. Cancer Res. 2005;65:1027-34 pubmed..SL0101 will provide a powerful new tool to dissect the molecular functions of RSK in cancer cells. ..
- Drobic B, Espino P, Davie J. Mitogen- and stress-activated protein kinase 1 activity and histone h3 phosphorylation in oncogene-transformed mouse fibroblasts. Cancer Res. 2004;64:9076-9 pubmed
- Smith K, Carter P, Bridges A, Horrocks P, Lewis C, Pettman G, et al. The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein. Structure. 2004;12:1067-77 pubmed..The new three-stranded beta sheet occupies a position equivalent to the N terminus of the alphaC helix in active protein kinases. ..
- Vermeulen L, De Wilde G, Van Damme P, Vanden Berghe W, Haegeman G. Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J. 2003;22:1313-24 pubmed..This effect represents, together with phosphorylation of nucleosome components such as histone H3, an essential step leading to selective transcriptional activation of NF-kappaB-dependent gene expression. ..
- Carriere A, Ray H, Blenis J, Roux P. The RSK factors of activating the Ras/MAPK signaling cascade. Front Biosci. 2008;13:4258-75 pubmed..The recent identification of specific RSK inhibitors will likely help addressing the biological functions of the RSK isoforms and their contributions in pathological conditions. ..
- Zhu J, Blenis J, Yuan J. Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc Natl Acad Sci U S A. 2008;105:6584-9 pubmed publisher..Our study provides a direct link between the growth factor signaling pathways regulated by PI3 kinase/Akt and MAP kinases with Myc-mediated transcription. ..
- Zhang H, Li L, Papadopoulou N, Hodgson G, Evans E, Galbraith M, et al. Mitogen-induced recruitment of ERK and MSK to SRE promoter complexes by ternary complex factor Elk-1. Nucleic Acids Res. 2008;36:2594-607 pubmed publisher..Taken together, our data add to the body of evidence implying that ERK and related MAPKs may fulfil a generic role at the promoters of acutely regulated genes. ..
- Butcher G, Lee B, Cheng H, Obrietan K. Light stimulates MSK1 activation in the suprachiasmatic nucleus via a PACAP-ERK/MAP kinase-dependent mechanism. J Neurosci. 2005;25:5305-13 pubmed..Together, these data identify MSK1 as both a downstream target of the MAPK cascade within the SCN and a regulator of clock gene expression. ..
- Ikuta M, Kornienko M, Byrne N, Reid J, Mizuarai S, Kotani H, et al. Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors. Protein Sci. 2007;16:2626-35 pubmed..Structures of RSK1 ligand complexes offer insights into the design of novel anticancer agents and into the regulation of the catalytic activity of RSKs. ..
- Cho Y, Yao K, Kim H, Kang B, Zheng D, Bode A, et al. Ribosomal S6 kinase 2 is a key regulator in tumor promoter induced cell transformation. Cancer Res. 2007;67:8104-12 pubmed..These results showed that RSK2 is a key regulator for cell transformation induced by tumor promoters such as EGF and TPA. ..
- Roux P, Shahbazian D, Vu H, Holz M, Cohen M, Taunton J, et al. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem. 2007;282:14056-64 pubmed..These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery. ..
- Strelkov I, Davie J. Ser-10 phosphorylation of histone H3 and immediate early gene expression in oncogene-transformed mouse fibroblasts. Cancer Res. 2002;62:75-8 pubmed..We propose that persistent activation of the Ras-MAPK pathway and MSK1 resulting in the elevation of phosphorylated H3 levels may contribute to the aberrant gene expression observed in the oncogene-transformed cells. ..
- Wang X, Li W, Williams M, Terada N, Alessi D, Proud C. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J. 2001;20:4370-9 pubmed..In contrast, regulation of eEF2 by stimuli that activate Erk is insensitive to rapamycin, but blocked by inhibitors of MEK/Erk signalling, consistent with the involvement of p90(RSK1). ..
- Arthur J, Cohen P. MSK1 is required for CREB phosphorylation in response to mitogens in mouse embryonic stem cells. FEBS Lett. 2000;482:44-8 pubmed..Thus MSK1 is required for CREB and ATF1 phosphorylation after mitogenic stimulation of ES cells. ..
- Joel P, Smith J, Sturgill T, Fisher T, Blenis J, Lannigan D. pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Mol Cell Biol. 1998;18:1978-84 pubmed..Taken together, our results strongly suggest that pp90rsk1 phosphorylates Ser-167 of the human ER in vivo and that Ser-167 aids in regulating the transcriptional activity of AF-1 in the ER. ..
- Chen R, Sarnecki C, Blenis J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol. 1992;12:915-27 pubmed
- Frodin M, Antal T, Dummler B, Jensen C, Deak M, Gammeltoft S, et al. A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation. EMBO J. 2002;21:5396-407 pubmed..Sequence conservation suggests that this mechanism is a key feature in activation of >40 human AGC kinases. ..
- Sapkota G, Kieloch A, Lizcano J, Lain S, Arthur J, Williams M, et al. Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell vrowth. J Biol Chem. 2001;276:19469-82 pubmed..In contrast, a mutant of LKB1 that cannot be prenylated was still able to suppress the growth of cells. ..
- Frodin M, Jensen C, Merienne K, Gammeltoft S. A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1. EMBO J. 2000;19:2924-34 pubmed..Our results suggest a novel regulatory mechanism based on phosphoserine-mediated recruitment of PDK1 to RSK2, leading to coordinated phosphorylation and activation of PDK1 and RSK2. ..
- Williams M, Arthur J, Balendran A, Van Der Kaay J, Poli V, Cohen P, et al. The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells. Curr Biol. 2000;10:439-48 pubmed..Another kinase phosphorylates PKB at its hydrophobic motif in PDK1(-/-) cells. PDK1 phosphorylates the hydrophobic motif of p70 S6 kinase either directly or by activation of another kinase. ..
- Thomson S, Clayton A, Hazzalin C, Rose S, Barratt M, Mahadevan L. The nucleosomal response associated with immediate-early gene induction is mediated via alternative MAP kinase cascades: MSK1 as a potential histone H3/HMG-14 kinase. EMBO J. 1999;18:4779-93 pubmed..Thus, the nucleosomal response is an invariable consequence of ERK and p38 but not JNK/SAPK activation, and MSK1 potentially provides a link to complete the circuit between cell surface and nucleosome. ..
- De Cesare D, Jacquot S, Hanauer A, Sassone Corsi P. Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene. Proc Natl Acad Sci U S A. 1998;95:12202-7 pubmed..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. ..
- Deak M, Clifton A, Lucocq L, Alessi D. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 1998;17:4426-41 pubmed..These findings, together with other observations, suggest that MSK1 may mediate the growth-factor and stress-induced activation of CREB. ..