Ribosomal subunit kinase-2 is required for growth factor-stimulated transcription of the c-
            <i>Fos</i>
            gene

Brüning, Jens C.; Gillette, Jennifer A.; Zhao, Yi; Bjorbaeck, Christian; Kotzka, Jörg; Knebel, Birgit; Avci, Haluk; Hanstein, Bettina; Lingohr, Philipp; Moller, David E.; Krone, Wilhelm; Kahn, C. Ronald; Müller‐Wieland, Dirk

doi:10.1073/pnas.97.6.2462

Cited by 71 publications

(62 citation statements)

References 25 publications

(29 reference statements)

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“…However, precise substrates for each member of the family are less well understood. RPS6KA3 was shown to be inactivated by mutations in the X-linked disorder Coffin-Lowry syndrome yet the highly related RPS6KA1 and RPS6KA2 kinases were found to be expressed at normal levels in these patients (Trivier et al, 1996;Bruning et al, 2000). This has been further confirmed by the generation of RPS6KA3 À/À mice (Dufresne et al, 2001).…”

Section: Discussionmentioning

confidence: 80%

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: 80%

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

et al. 2006

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“…To determine the functional significance of this interaction, we obtained fibroblasts from RSK2ϩ͞ϩ and RSK2Ϫ͞Ϫ mice (14). We performed microarray studies to identify endogenously expressed GPCRs in these cell lines (Table 3, which is published as supporting information on the PNAS web site) and assessed signaling at a subset of the identified receptors.…”

Section: Rsk2 Modulates Gpcr Signalingmentioning

confidence: 99%

“…RSK2 knockout mice show diminished memory, coordination deficits, and growth retardation (13), providing a model for the study of CLS. In addition, RSK2 knockout mice demonstrate alterations in insulin-and exercise-stimulated ERK͞MAPK signal transduction (13) and in transcription factor phosphorylation (14). Because the transcription factor cAMP response-elementbinding protein (CREB) is implicated in learning and memory (15), changes in the CREB pathway associated with RSK2 deficiency may lead, in part, to the symptoms of CLS.…”

mentioning

confidence: 99%

p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling

Sheffler¹,

Kroeze²,

Garcia

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) are essential for normal central CNS function and represent the proximal site(s) of action for most neurotransmitters and many therapeutic drugs, including typical and atypical antipsychotic drugs. Similarly, protein kinases mediate many of the downstream actions for both ionotropic and metabotropic receptors. We report here that genetic deletion of p90 ribosomal S6 kinase 2 (RSK2) potentiates GPCR signaling. Initial studies of 5-hydroxytryptamine (5-HT) 2A receptor signaling in fibroblasts obtained from RSK2 wild-type (؉͞؉) and knockout (؊͞؊) mice showed that 5-HT 2A receptor-mediated phosphoinositide hydrolysis and both basal and 5-HT-stimulated extracellular signal-regulated kinase 1͞2 phosphorylation are augmented in RSK2 knockout fibroblasts. Endogenous signaling by other GPCRs, including P2Y-purinergic, PAR-1-thrombinergic, ␤1-adrenergic, and bradykinin-B receptors, was also potentiated in RSK2-deficient fibroblasts. Importantly, reintroduction of RSK2 into RSK2؊͞؊ fibroblasts normalized signaling, thus demonstrating that RSK2 apparently modulates GPCR signaling by exerting a ''tonic brake'' on GPCR signal transduction. Our results imply the existence of a novel pathway regulating GPCR signaling, modulated by downstream members of the extracellular signal-related kinase͞ mitogen-activated protein kinase cascade. The loss of RSK2 activity in humans leads to Coffin-Lowry syndrome, which is manifested by mental retardation, growth deficits, skeletal deformations, and psychosis. Because RSK2-inactivating mutations in humans lead to Coffin-Lowry syndrome, our results imply that alterations in GPCR signaling may account for some of its clinical manifestations.serotonin ͉ signal transduction G protein-coupled receptors (GPCRs) represent proximal molecular targets for most neurotransmitters, many psychiatric medications, and some drugs of abuse (1). Thus, for instance, antipsychotic and antidepressant medications interact with literally dozens of GPCRs (2). Drugs of abuse tend to have a more restricted pattern of interaction, with morphine being selective for -opioid receptors, and salvinorin A being selective for -opioid sites (3). GPCRs can also function as coreceptors for viruses; thus, the 5-hydroxytryptamine (5-HT) 2A serotonin receptor acts as a coreceptor for the JC virus, the agent responsible for progressive multifocal leukoencepalpathy (4). Agonist-induced activation of GPCRs frequently leads to a complex cascade of intracellular signaling involving arrestins and members of the mitogen-activated protein kinase (MAPK) cascade (5).The p90 ribosomal S6 kinases (RSK)1-4 are downstream members of the extracellular signal-regulated kinase (ERK)͞MAPK cascade, which contain two separate kinase domains connected by a linker domain (Fig. 1B) (6). Multiple phosphorylation events by upstream protein kinases are necessary for the complete activation of the N-terminal kinase (NTK) domain of RSKs (Fig. 1B). The NTK of RSK2 phosphorylates a broad range of substrates, including cAMP r...

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“…RSK with ERK-docking motif phosphorylates serum response factor and contributes to transcriptional activation of c-Fos. c-Fos protein is stabilized by ERK and RSK phosphorylation and functions as part of the c-Fos-JUN activator protein-1 complex to activate expression of cyclin D, which contributes to G 1 /S phase progression (51). In meiosis, RSK without ERK-docking motif phosphorylates and inactivates Myt1, a membrane-associated kinase that phosphorylates cdc2 on Tyr and Thr residues (52).…”

Section: Discussionmentioning

confidence: 99%

“…RSK isoforms control cell proliferation by regulating mediators of the cell cycle (51,52). RSK with ERK-docking motif phosphorylates serum response factor and contributes to transcriptional activation of c-Fos.…”

Section: Discussionmentioning

confidence: 99%

Two p90 Ribosomal S6 Kinase Isoforms Are Involved in the Regulation of Mitotic and Meiotic Arrest in Artemia

Duan

Zhang

Chen

et al. 2014

Journal of Biological Chemistry

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Background: Ribosomal S6 kinase (RSK) plays important roles in meiosis and mitosis. Results: Ar-Rsk1 promoted cdc2 phosphorylation and thereby meiotic arrest, whereas Ar-Rsk2 knockdown resulted in mitotic arrest. Conclusion: Ar-Rsk1, which lacks an ERK-docking motif, controls meiotic arrest, whereas Ar-Rsk2, which has an ERK-docking motif, controls mitotic arrest. Significance: The data provide insight into the functions of RSK isoforms.

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Ribosomal subunit kinase-2 is required for growth factor-stimulated transcription of the c- Fos gene

Cited by 71 publications

References 25 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

p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling

Two p90 Ribosomal S6 Kinase Isoforms Are Involved in the Regulation of Mitotic and Meiotic Arrest in Artemia

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