p90 ribosomal S6 kinase 2 is associated with and dephosphorylated by protein phosphatase 2Cδ

Doehn, Ulrik; Gammeltoft, Steen; Shen, Shi-Hsiang; Jensen, Claus Munk

doi:10.1042/bj20040948

Cited by 28 publications

(23 citation statements)

References 42 publications

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“…However, activation of RSK promotes its interaction with the PKA catalytic subunit, which was found to decrease the ability of cAMP to stimulate PKA. RSK inactivation may require the phosphatase PP2C␦, which was found to associate with RSK1 to -4 (92). Inactivation of RSK1 may also involve its autophosphorylation at Ser732, which was found to promote ERK/RSK dissociation and correlate with reduced RSK kinase activity (302).…”

Section: Rskmentioning

confidence: 99%

Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

Cargnello

Roux

2011

Microbiol Mol Biol Rev

2,523

1,619

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SUMMARY The mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs by relaying extracellular signals to intracellular responses. In mammals, there are more than a dozen MAPK enzymes that coordinately regulate cell proliferation, differentiation, motility, and survival. The best known are the conventional MAPKs, which include the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1 to 3 (JNK1 to -3), p38 (α, β, γ, and δ), and ERK5 families. There are additional, atypical MAPK enzymes, including ERK3/4, ERK7/8, and Nemo-like kinase (NLK), which have distinct regulation and functions. Together, the MAPKs regulate a large number of substrates, including members of a family of protein Ser/Thr kinases termed MAPK-activated protein kinases (MAPKAPKs). The MAPKAPKs are related enzymes that respond to extracellular stimulation through direct MAPK-dependent activation loop phosphorylation and kinase activation. There are five MAPKAPK subfamilies: the p90 ribosomal S6 kinase (RSK), the mitogen- and stress-activated kinase (MSK), the MAPK-interacting kinase (MNK), the MAPK-activated protein kinase 2/3 (MK2/3), and MK5 (also known as p38-regulated/activated protein kinase [PRAK]). These enzymes have diverse biological functions, including regulation of nucleosome and gene expression, mRNA stability and translation, and cell proliferation and survival. Here we review the mechanisms of MAPKAPK activation by the different MAPKs and discuss their physiological roles based on established substrates and recent discoveries.

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Section: Rskmentioning

confidence: 99%

Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

Cargnello

Roux

2011

Microbiol Mol Biol Rev

2,523

1,619

View full text Add to dashboard Cite

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“…Of particular interest, RSK (and in many cases also MSK) interactions with the acetylase CBP, the phosphatase PP2C, or 14-3-3h proteins have been found to regulate its subcellular localization and restrict its activities in time and space (31,(49)(50)(51). Further experiments will be required to unravel genistein effects on spatiotemporal dynamics of MSK(RSK)-cofactor complexes in relation to selective NF-nB-dependent gene expression.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Mitogen- and Stress-Activated Protein Kinase-1–Driven Nuclear Factor-κB Gene Expression by Soy Isoflavones Does Not Require Estrogenic Activity

et al. 2006

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We have analyzed in molecular detail how soy isoflavones (genistein, daidzein, and biochanin A) suppress nuclear factor-KB (NF-KB)-driven interleukin-6 (IL6) expression. In addition to its physiologic immune function as an acute stress cytokine, sustained elevated expression levels of IL6 promote chronic inflammatory disorders, aging frailty, and tumorigenesis. Our results in estrogen-unresponsive fibroblasts, mitogen-and stress-activated protein kinase (MSK) knockout cells, and estrogen receptor (ER)-deficient breast tumor cells show that phytoestrogenic isoflavones can selectively block nuclear NF-KB transactivation of specific target genes (in particular IL6), independently of their estrogenic activity. This occurs via attenuation of mitogen-activated protein/ extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activity, which further down-regulates MSK-dependent NF-KB p65 and histone H3 phosphorylation. As constitutive NF-KB and MSK activity are hallmarks of aggressive metastatic ER-deficient breast cancer, the MSK signaling pathway may become an attractive target for chemotherapy.

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“…Although, PP2C␦ has been shown to associate with RSK1-4 presumably via the N-terminal kinase of RSKs (42), its role in dephosphorylation of RSKs in intact cells has not been demonstrated. In this context, our findings identify PP2A as the first phosphatase that dephosphorylates RSK1.…”

Section: Pp2a Exists In a Complex With Rsk1⅐pka⅐d-akap1 And Ht31mentioning

confidence: 99%

The PKARIα Subunit of Protein Kinase A Modulates the Activation of p90RSK1 and Its Function

Chaturvedi

Cohen

Taunton

et al. 2009

Journal of Biological Chemistry

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Cyclic AMP-dependent protein kinase (PKA) 3 plays a pivotal role in manifesting an array of biological actions ranging from cell proliferation and tumorigenesis to increased inotropic and chronotropic effects in the heart as well as regulation of long term potentiation and memory. The PKA holoenzyme is a heterotetramer and consists of two catalytic (PKAc) subunits bound to a dimer of regulatory subunits. To date, four isoforms of the PKAc (PKAc␣, PKAc␤, PKAc␥, and PKAc␦) and four isoforms of the regulatory subunits (RI␣, RI␤, RII␣, and RII␤) have been described (1). The various isoforms of PKA subunits are expressed differently in a tissue-and cell-specific manner (2). In addition to binding and inhibiting the activity of PKAc via their pseudo substrate region (3-6), the R subunits also interact with PKA-anchoring proteins (AKAPs) and facilitate the localization of PKA in specific subcellular compartments (7,8). More than 50 AKAP family members have been described, and although most of these have a higher affinity for the RII subunits (9), certain AKAPs such as D-AKAP1 and D-AKAP2 preferentially bind the PKARI␣ subunit (10 -12). Because the AKAPs also bind other signaling molecules such as phosphatases (PP2B) and kinases (protein kinase C), they act as scaffolds to organize and integrate specific signaling events within specific compartments in the cells (7,8,13,14).We have shown that the PKARI␣ and PKAc␣ subunits of PKA interact with the inactive and active forms of p90 RSK1 (RSK1), respectively (15). Binding of inactive RSK1 to PKARI␣ decreases the interactions between PKARI␣ and PKAc, whereas the association of active RSK1 with PKAc increases interactions between PKARI␣ and PKAc such that larger amounts of cAMP are required to activate PKAc in the presence of active RSK1 (15). Moreover, the indirect (via subunits of PKA) interaction of RSK1 with AKAPs is required for the nuclear localization of active RSK1 (15), and disruption of the interactions of RSK1⅐PKA complex from AKAPs results in increased cytoplasmic distribution of active RSK1 with a concomitant increase in phosphorylation of its cytosolic substrates such as BAD and reduced cellular apoptosis (15). These findings show the functional and biological significance of RSK1⅐ PKA⅐AKAP interactions.Besides inhibiting PKAc activity, the physiological role of PKARI␣ is underscored by the findings that mutations in the PKAR1A gene that result in haploinsufficiency of PKARI␣ are

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p90 ribosomal S6 kinase 2 is associated with and dephosphorylated by protein phosphatase 2Cδ

Cited by 28 publications

References 42 publications

Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

Attenuation of Mitogen- and Stress-Activated Protein Kinase-1–Driven Nuclear Factor-κB Gene Expression by Soy Isoflavones Does Not Require Estrogenic Activity

The PKARIα Subunit of Protein Kinase A Modulates the Activation of p90RSK1 and Its Function

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