A Novel Ribosomal S6-Kinase (RSK4; RPS6KA6) Is Commonly Deleted in Patients with Complex X-Linked Mental Retardation

Helm, L.J.M. van den; Kissing, J.; Duijnhoven, G.C.F. van; Poppelaars, F.; Chelly, Jamel; Moraine, Claude; Hamel, B.C.J.; Heilbronner, H.; Pander, Hans‐Jürgen; Brunner, Han G.; Ropers, Hans‐Hilger; Cremers, Frans P.M.; Bokhoven, Hans van

doi:10.1006/geno.1999.6004

Cited by 110 publications

(97 citation statements)

References 71 publications

(77 reference statements)

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“…Initially, RPS6KA1 (p90 Rsk-1) and RPS6KA3 (p90 Rsk-2) were identified (Frodin and Gammeltoft, 1999). Subsequently, RPS6KA2 (p90 Rsk-3) was isolated and more recently, RPS6KA6 (p90 Rsk-4) (Moller et al, 1994;Zhao et al, 1995;Yntema et al, 1999;Dummler et al, 2005). RPS6KA4 (Msk-1) and RPS6KA5 (Msk-2) are less homologous to the first four members of the RSK family.…”

Section: Discussionmentioning

confidence: 99%

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

et al. 2006

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We had previously defined by allele loss studies a minimal region at 6q27 (between D6S264 and D6S297) to contain a putative tumour suppressor gene. The p90 ribosomal S6 kinase-3 gene (p90 Rsk-3, RPS6KA2) maps in this interval. It is a serine-threonine kinase that signals downstream of the mitogen-activated protein kinase pathway. It is expressed in normal ovarian epithelium, whereas reduced or absent in tumours or cell lines. We show that RPS6KA2 is monoallelically expressed in the ovary suggesting that loss of a single expressed allele is sufficient to cause complete loss of expression in cancer cells. Further, we have identified two new isoforms of RPS6KA2 with an alternative start codon. Homozygous deletions were identified within the RPS6KA2 gene in two cell lines. Re-expression of RPS6KA2 in ovarian cancer cell lines suppressed colony formation. In UCI101 cells, the expression of RPS6KA2 reduced proliferation, caused G1 arrest, increased apoptosis, reduced levels of phosphorylated extracellular signal-regulated kinase and altered other cell cycle proteins. 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.

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Section: Discussionmentioning

confidence: 99%

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

et al. 2006

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“…The rsk2 and rsk3 transcripts and proteins are expressed in most tissues, including heart, brain, placenta, liver, kidney, and pancreas, with predominant expression in skeletal muscle (43,243,247). The rsk4 transcript is also expressed ubiquitously but was shown to be present in high levels in fetal tissues and in adult brain and kidney (241). Northern analysis also revealed the presence of two secondary rsk4 transcripts (5 and 9 kb), but whether these transcripts result from alternative splicing or alternative polyadenylation remains unknown (241).…”

Section: Vol 68 2004 Mapk-activated Protein Kinases 327mentioning

confidence: 99%

“…The rsk4 transcript is also expressed ubiquitously but was shown to be present in high levels in fetal tissues and in adult brain and kidney (241). Northern analysis also revealed the presence of two secondary rsk4 transcripts (5 and 9 kb), but whether these transcripts result from alternative splicing or alternative polyadenylation remains unknown (241). Interestingly, the reported mouse and rat RSK4 sequences contain an additional N-terminal region that is not found in human RSK4 or in other RSK family members.…”

Section: Vol 68 2004 Mapk-activated Protein Kinases 327mentioning

confidence: 99%

ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

Roux

Blenis

2004

Microbiol Mol Biol Rev

2,172

1,861

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Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries

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“…In addition, RSKs contain a regulatory linker sequence connecting the two kinase domains and an extended C-terminal tail. RSKs comprise RSK1-RSK3, which are stimulated through the ERK pathway (1)(2)(3)(4)(5)(6); the more recently identified mitogen-and stress-activated protein kinase type 1 and RSKB, which are activated by both the p38 and ERK pathways (7)(8)(9); and RSK4 (10). RSKs are involved in many diverse functions, such as regulation of glycogen metabolism by phosphorylating glycogen synthase kinase-3 and the G-subunit of protein phosphatase 1, and cell survival of cerebellar neurons through phosphorylation of BAD (reviewed in Refs.…”

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confidence: 99%

“…Deficient mutants of RSK2 in man are linked to Coffin-Lowry syndrome, characterized by mental retardation and malformations (19). Deletion of RSK4 is common in patients with X-linked mental retardation (10). Interestingly, RSKB maps to the BBS1 locus (20), which is associated with Bardet-Biedl syndrome with manifestations reminiscent of Coffin-Lowry syndrome (21), and may be a candidate BBS gene.…”

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confidence: 99%

C-terminal Elements Control Location, Activation Threshold, and p38 Docking of Ribosomal S6 Kinase B (RSKB)

Tomás-Zuber¹,

Mary²,

Lamour³

et al. 2001

Journal of Biological Chemistry

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RSKB, a p90 ribosomal S6 protein kinase with two catalytic domains, is activated by p38-and extracellular signal-regulated kinase mitogen-activated protein kinase pathways. The sequences between the two catalytic domains and of the C-terminal extension contain elements that control RSKB activity. The C-terminal extension of RSKB presents a putative bipartite 713 KRX 14 KRRKQKLRS 737 nuclear location signal. The distinct cytoplasmic and nuclear locations of various C-terminal truncation mutants supported the hypothesis that the nuclear location signal was essential to direct RSKB to the nuclear compartment. The 725 APLA-KRRKQKLRS 737 sequence also was essential for the intermolecular association of RSKB with p38. The activation of RSKB through p38 could be dissociated from p38 docking, because RSKB truncated at Ser 681 strongly responded to p38 pathway activity. Interestingly, ⌬ 725-772 -RSKB was nearly nonresponsive to p38. Sequence alignment with the autoinhibitory C-terminal extension of Ca ؉2 /calmodulin-dependent protein kinase I predicted a conserved regulatory 708 AFN 710 motif. Alanine mutation of the key Phe 709 residue resulted in strongly elevated basal level RSKB activity. A regulatory role also was assigned to Thr 687 , which is located in a mitogen-activated protein kinase phosphorylation consensus site. These findings support that the RSKB C-terminal extension contains elements that control activation threshold, subcellular location, and p38 docking.The p90 ribosomal S6 protein kinases (RSKs) 1 are a family of Ser/Thr protein kinases composed of two catalytic domains, each with canonical ATP-binding site and activation loop sequences. In addition, RSKs contain a regulatory linker sequence connecting the two kinase domains and an extended C-terminal tail. RSKs comprise RSK1-RSK3, which are stimulated through the ERK pathway (1-6); the more recently identified mitogen-and stress-activated protein kinase type 1 and RSKB, which are activated by both the p38 and ERK pathways (7-9); and RSK4 (10). RSKs are involved in many diverse functions, such as regulation of glycogen metabolism by phosphorylating glycogen synthase kinase-3 and the G-subunit of protein phosphatase 1, and cell survival of cerebellar neurons through phosphorylation of BAD (reviewed in Refs. 11-13). RSKs function in the control of M phase entry of oocytes during meiosis and chromatin remodeling through histone H3 phosphorylation (14, 15). Furthermore, RSKs participate in the regulation of transcription factors and coregulators, such as CREB (3-5, 7, 8), CREB-binding protein and p300 (16), c-Fos (17), and estrogen receptor (18). Deficient mutants of RSK2 in man are linked to Coffin-Lowry syndrome, characterized by mental retardation and malformations (19). Deletion of RSK4 is common in patients with X-linked mental retardation (10). Interestingly, RSKB maps to the BBS1 locus (20), which is associated with Bardet-Biedl syndrome with manifestations reminiscent of Coffin-Lowry syndrome (21), and may be a candidate BBS gene.Many Ser/Thr-ki...

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A Novel Ribosomal S6-Kinase (RSK4; RPS6KA6) Is Commonly Deleted in Patients with Complex X-Linked Mental Retardation

Cited by 110 publications

References 71 publications

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

C-terminal Elements Control Location, Activation Threshold, and p38 Docking of Ribosomal S6 Kinase B (RSKB)

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