Note | Human RPS6KA6 gene codes for the protein RSK4, a serine- threonine kinase with 745 amino acids, also a member of the 90 kDa ribosomal S6 kinase (RSK) family which includes other three members RSK1, RSK2 and RSK3 (Yntema et al., 1999; Dümmler et al., 2005; Anjum and Blenis, 2008; Serra et al., 2013). |
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| The basic structure of the RSK4. The RSK4 protein includes two kinases domains: amino-terminal kinase domain (NTKD) and carboxyl-terminal kinase domain (CTKD), a linker region and amino- and carboxyl-terminal tails. The NTKD is responsible for substrate phosphorylation and CTKD regulates sutophosphorylation of the RSK4. The two kinase domains are connected by a linker region which is about 100 amino acids containing essential regulatory domains including hydrophobic and turn motifs, involved in the activation of NTKD. An ERK-docking motif, known also as the D domain, is located in the carboxyl-terminal tail (Dümmler et al., 2005; Anjum and Blenis, 2008; Romeo et al., 2012). |
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Description | RSK4 is a serine- threonine kinase and there are six phosphorylation sites in RSK4: Ser232, Thr368, Ser372, Ser389, Thr581, and Ser742. Upon activation of the cell surface receptors, ERK first bound to the ERK-docking motif in the carboxyl-terminal and phosphorylates Ser372 in the linker region and Thr581 in the CTKD. Phosphorylation of Thr581 activates CTK which autophosphorylates RSK4 at Ser389 in the linker region. Phosphorylation of Ser389 recruites and activiates PDK1 which phosphorylates Ser232 in NTKD. After dissociation of PDK1 from RSK, the Ser386 phosphorylated motif interacts with NTKD and activates the NTK in synergy with phosphor-Ser232. The phosphorylation of Ser372 increases the activity of NTK. Thr368 is phosphorylated by ERK and Ser742 can be phosphorylated by activated NTK, which leads to the association of RSK and ERK, serving as an inhibitory feedback mechanism to "shut off" the process (Dümmler et al., 2005). The CTKD activity of RSK1, RSK2 and RSK4 can be regulated by the irreversible inhibitor, pyrrolopyrimidine FMK (Z-VAD-FMK, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone) (Romeo et al., 2012). |
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| The activation of the RSK4 family protein. All RSK family membranes including RSK4 are involved in MAPK pathways and can be activated by various molecules including growth factors, neurotransmitters, hormones, phorbol esters. First, activation of cell surface receptors creates docking site for adaptor molecules like growth factor receptor-bound protein-2 (GRB2). GRB2 links the receptor to the guanine nucleotide-exchange factor son of sevenless (SOS). SOS catalyses GDP release and GTP binding to the small G-protein Ras. The GTP-bound Ras then binds to the Raf protein kinases. Upon the activation of Raf, it activates MAPK kinase (MEK), then downstream extracellular signal-regulated kinase (ERK). All four RSK family members are directly phosphorylated and activated by ERK1/2. RSKs are also phosphorylated by 3'-phosphoinositide-dependent kinase-1 (PDK1) which is a serine-threonine kinase. Activated RSKs can then phosphorylate their substrates via serine and threonine sites (Anjum and Blenis, 2008). |
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Expression | RSK4 expression is low in both mouse and human embryonic and adult tissues compared with other three RSK family members. RSK4 mRNA was detected in the brain, cerebellum, heart, kidney and skeletal muscle, but not in other tissues such as lung, liver, pancreas and adipose. Specifically, RSK4 was found to be ubiquitously expressed at a low level through mouse development, and it is more highly expressed in specific phases of embryogenesis such as egg cylinder, gastrula and organ genesis (Kohn et al., 2003; Lleonart et al., 2006; Romeo et al., 2012). |
Localisation | RSK is predominantly located in cytosol, and contrary to other RSKs, its expression is relatively low and does not significantly accumulate in the nucleus after mitogenic stimulation (Dümmler et al., 2005; Romeo et al., 2012). |
Function | Recent studies showed RSK4 can be either oncogenic or tumor suppressive depending on many factors, and Cyclin D1 inhibited RSK4 expression and serum starvation enhanced the inhibition. RSK4 can induce cellular senescence which is mediated by p21. Also, inhibition of RSK4 causes bypass of cellular senescence induced by stress or oncogene, suggesting RSK4 inhibition may be an important factor in facilitating cell transformation. (López-Vicente et al., 2011). shRNA against RPS6KA6 bypassed p53-dependent G1 cell cycle arrest and suppressed mRNA expression of cyclin-dependent kinase inhibitor p21cip1, suggesting RSK4 is needed for growth arrest induced by p53 (Berns et al., 2004). In addition, RSK4 is identified to be an inhibitor of fibroblast growth factor (FGF)-Ras-ERK signal transduction. RSK4 plays an inhibitory role during embryogenesis by suppressing receptor tyrosine kinase signaling (López-Vicente et al., 2009). |
Homology | The RSK family members share 73-80% amino acids similarity to each other and are mostly different in their amino- and carboxyl-terminal sequences (Romeo et al., 2012). Difference from other RSK members whose activation needs the stimulation by growth factors, RSK4 can be constitutively activated under serum-starved condition without growth factor. The constitutive activation is due to constitutive phosphorylation of Ser232, Ser372 and Ser389 (Dümmler et al., 2005). PDK1 is required for mitogenic stimulation of RSK1-3, however, RSK4 does not appear to require PDK1 to maintain its high basal activity (Romeo et al., 2012). Unlike other three family members, RSK4 expression can disrupt mouse mesoderm formation induced by the FGF-Ras-ERK signaling pathway (Myers et al., 2004). |
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Entity | Breast cancer |
Note | RSK4 is highly expressed and has anti-invasive and anti-metastatic activities in breast cancer. Exogenous expression of RSK4 resulted in decreased breast cancer cell proliferation and increased accumulation of cells in G0-G1 phase of the cell cycle, also with enhanced expression several tumor suppressor genes: retinoblastoma protein, retinoblastoma-associated 46 kDa protein (RbAp46), and p21 protein (Thakur et al., 2007; Thakur et al., 2008). In addition, RSK4 expression enhances breast cancer cell survival upon PI3K/mTOR inhibitors treatment through inhibition of apoptosis and up-regulation of protein translation. Adding MEK- or RSK-specific inhibitors can overcome the RSK4 mediated resistance, thus, combination of RSK and PI3K pathway inhibitors may overcome the resistance mediated by RSK4 in breast cancer (Serra et al., 2013). |
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Entity | Colon, kidney cancer and melanoma |
Note | RSK4 is down-regulated in colon carcinomas, renal cell carcinomas and colon adenomas. Overexpression of RSK4 induced cell arrest and senescence features in normal fibroblasts and malignant colon carcinoma cell lines. In addition, RSK4 is up-regulated in both replicative and stress-induced senescence and RSK4 inhibition induces senescence resistance in colon carcinoma cells, suggesting RSK4 may be a tumor suppressor gene by regulating senescence induction and inviting cell proliferation in colon carcinogenesis and renal cell carcinomas (Myers et al., 2004). RSK4 expression causes Sunitinib resistance in kidney carcinoma and melanoma cells, thus, RSK4 may be a potential resistance marker in Sunitinib therapy and a potential target for new drug development to overcome Sunitinib resistance (Llenaont et al., 2006; Bender and Ullrich, 2012). |
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Entity | Endometrial cancer |
Note | RSK4 is frequently hypermethylated in endometrial cancer and RSK4 methylation is significantly associated with tumor grade, with higher grade tumors having lower levels of methylation. Thus, RSK4 appears to be epigenetically silenced in endometrial cancer as evidenced by hypermethylation (Dewdney et al., 2011). |
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Entity | X-linked mental retardation |
Note | RPS6KA6 gene is commonly deleted in complex X-linked mental retardation patients (Yntema et al., 1999). |
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Entity | Autism spectrum disorder |
Note | RPS6KA6 plays a role in brain development and could be associated with mental retardation. RSP6KA6 is located in the chromosomal region, which is commonly deleted in males with mental retardation. Its mutation may be associated with autism spectrum disorders (Kantojärvi et al., 2011). |
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Entity | AIDS |
Note | SNP rs5968255, located at human Xq21.1 in a conserved sequence element near the RPS6KA6 and CYLC1 genes, was identified as a significant genetic determinant of AIDS progression in HIV infected women. However, whether RPS6KA6 gene is functionally involved in the observed phenotype is not clear (Siddiqui et al., 2009). |
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The RSK family of kinases: emerging roles in cellular signalling. |
Anjum R, Blenis J. |
Nat Rev Mol Cell Biol. 2008 Oct;9(10):747-58. doi: 10.1038/nrm2509. (REVIEW) |
PMID 18813292 |
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PRKX, TTBK2 and RSK4 expression causes Sunitinib resistance in kidney carcinoma- and melanoma-cell lines. |
Bender C, Ullrich A. |
Int J Cancer. 2012 Jul 15;131(2):E45-55. doi: 10.1002/ijc.26486. Epub 2012 Feb 28. |
PMID 22020623 |
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A large-scale RNAi screen in human cells identifies new components of the p53 pathway. |
Berns K, Hijmans EM, Mullenders J, Brummelkamp TR, Velds A, Heimerikx M, Kerkhoven RM, Madiredjo M, Nijkamp W, Weigelt B, Agami R, Ge W, Cavet G, Linsley PS, Beijersbergen RL, Bernards R. |
Nature. 2004 Mar 25;428(6981):431-7. |
PMID 15042092 |
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Aberrant methylation of the X-linked ribosomal S6 kinase RPS6KA6 (RSK4) in endometrial cancers. |
Dewdney SB, Rimel BJ, Thaker PH, Thompson DM Jr, Schmidt A, Huettner P, Mutch DG, Gao F, Goodfellow PJ. |
Clin Cancer Res. 2011 Apr 15;17(8):2120-9. doi: 10.1158/1078-0432.CCR-10-2668. Epub 2011 Mar 3. |
PMID 21372219 |
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Functional characterization of human RSK4, a new 90-kDa ribosomal S6 kinase, reveals constitutive activation in most cell types. |
Dummler BA, Hauge C, Silber J, Yntema HG, Kruse LS, Kofoed B, Hemmings BA, Alessi DR, Frodin M. |
J Biol Chem. 2005 Apr 8;280(14):13304-14. Epub 2005 Jan 4. |
PMID 15632195 |
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Fine mapping of Xq11.1-q21.33 and mutation screening of RPS6KA6, ZNF711, ACSL4, DLG3, and IL1RAPL2 for autism spectrum disorders (ASD). |
Kantojarvi K, Kotala I, Rehnstrom K, Ylisaukko-Oja T, Vanhala R, von Wendt TN, von Wendt L, Jarvela I. |
Autism Res. 2011 Jun;4(3):228-33. doi: 10.1002/aur.187. Epub 2011 Feb 22. |
PMID 21384559 |
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Expression pattern of the Rsk2, Rsk4 and Pdk1 genes during murine embryogenesis. |
Kohn M, Hameister H, Vogel M, Kehrer-Sawatzki H. |
Gene Expr Patterns. 2003 May;3(2):173-7. |
PMID 12711546 |
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New p53 related genes in human tumors: significant downregulation in colon and lung carcinomas. |
LLeonart ME, Vidal F, Gallardo D, Diaz-Fuertes M, Rojo F, Cuatrecasas M, Lopez-Vicente L, Kondoh H, Blanco C, Carnero A, Ramon y Cajal S. |
Oncol Rep. 2006 Sep;16(3):603-8. |
PMID 16865262 |
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RSK4 inhibition results in bypass of stress-induced and oncogene-induced senescence. |
Lopez-Vicente L, Pons B, Coch L, Teixido C, Hernandez-Losa J, Armengol G, Ramon Y Cajal S. |
Carcinogenesis. 2011 Apr;32(4):470-6. doi: 10.1093/carcin/bgr003. Epub 2011 Jan 14. |
PMID 21239520 |
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Characterization of mouse Rsk4 as an inhibitor of fibroblast growth factor-RAS-extracellular signal-regulated kinase signaling. |
Myers AP, Corson LB, Rossant J, Baker JC. |
Mol Cell Biol. 2004 May;24(10):4255-66. |
PMID 15121846 |
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Regulation and function of the RSK family of protein kinases. |
Romeo Y, Zhang X, Roux PP. |
Biochem J. 2012 Jan 15;441(2):553-69. doi: 10.1042/BJ20110289. (REVIEW) |
PMID 22187936 |
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RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. |
Serra V, Eichhorn PJ, Garcia-Garcia C, Ibrahim YH, Prudkin L, Sanchez G, Rodriguez O, Anton P, Parra JL, Marlow S, Scaltriti M, Perez-Garcia J, Prat A, Arribas J, Hahn WC, Kim SY, Baselga J. |
J Clin Invest. 2013 Jun 3;123(6):2551-63. doi: 10.1172/JCI66343. Epub 2013 May 1. |
PMID 23635776 |
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X chromosomal variation is associated with slow progression to AIDS in HIV-1-infected women. |
Siddiqui RA, Sauermann U, Altmuller J, Fritzer E, Nothnagel M, Dalibor N, Fellay J, Kaup FJ, Stahl-Hennig C, Nurnberg P, Krawczak M, Platzer M. |
Am J Hum Genet. 2009 Aug;85(2):228-39. doi: 10.1016/j.ajhg.2009.07.013. |
PMID 19679225 |
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Aberrant expression of X-linked genes RbAp46, Rsk4, and Cldn2 in breast cancer. |
Thakur A, Rahman KW, Wu J, Bollig A, Biliran H, Lin X, Nassar H, Grignon DJ, Sarkar FH, Liao JD. |
Mol Cancer Res. 2007 Feb;5(2):171-81. |
PMID 17314274 |
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Anti-invasive and antimetastatic activities of ribosomal protein S6 kinase 4 in breast cancer cells. |
Thakur A, Sun Y, Bollig A, Wu J, Biliran H, Banerjee S, Sarkar FH, Liao DJ. |
Clin Cancer Res. 2008 Jul 15;14(14):4427-36. doi: 10.1158/1078-0432.CCR-08-0458. |
PMID 18628456 |
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A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation. |
Yntema HG, van den Helm B, Kissing J, van Duijnhoven G, Poppelaars F, Chelly J, Moraine C, Fryns JP, Hamel BC, Heilbronner H, Pander HJ, Brunner HG, Ropers HH, Cremers FP, van Bokhoven H. |
Genomics. 1999 Dec 15;62(3):332-43. |
PMID 10644430 |
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