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

Tomás-Zuber, Mar; Mary, Jean-Luc; Lamour, François; Bur, Daniel; Lesslauer, Werner

doi:10.1074/jbc.m005822200

Cited by 28 publications

(21 citation statements)

References 46 publications

(66 reference statements)

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“…Mutation of Thr 700 to alanine slightly increased the basal activity of MSK1, while mutation to aspartic acid increased the basal activity still further. A similar result has been shown for mutagenesis of the equivalent site of MSK2 [30], although this study did not directly establish that this residue could be phosphorylated. Mutation of the equivalent site in MNK1 or MNK2 has also been reported to give similar results [31,32]; however, while this site is phosphorylated in vitro by ERK [33], it was unclear from these studies if this was an in vivo phosphorylation site.…”

Section: Discussionsupporting

confidence: 49%

“…Consistent with this, C-terminal truncation of MSK2 has been reported to increase its basal activity [30], although this truncation also deletes nuclear localization and MAPK docking sequences. Such a mechanism would explain the increased basal activity of the Thr 700 MSK1 mutations; however, it would not explain why Thr 581 phosphorylation is reduced in these mutants.…”

Section: Discussionmentioning

confidence: 52%

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Identification of novel phosphorylation sites in MSK1 by precursor ion scanning MS

McCoy

Macdonald

Morrice

et al. 2007

Biochemical Journal

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MSK1 (mitogen-and stress-activated kinase 1) is a dual kinase domain protein that acts downstream of the ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 MAPK (mitogenactivated protein kinase) signalling pathways in cells. MSK1, and its related isoform MSK2, phosphorylate the transcription factors CREB (cAMP-response-element-binding protein) and ATF1 (activating transcription factor 1), and the chromatin proteins histone H3 and HMGN1 (high-mobility-group nucleosomalbinding protein 1) in response to either mitogenic stimulation or cellular stress. MSK1 activity is tightly regulated in cells, and activation requires the phosphorylation of MSK1 by either ERK1/2 or p38α. This results in activation of the C-terminal kinase domain, which then phosphorylates further sites in MSK1, leading to the activation of the N-terminal kinase domain and phosphorylation of substrates. Here, we use precursor ion scanning MS to identify five previously unknown sites in MSK1: Thr 630 , Ser 647 , Ser 657 , Ser 695 and Thr 700 . One of these sites, Thr 700 , was found to be a third site in MSK1 phosphorylated by the upstream kinases ERK1/2 and p38α. Mutation of Thr 700 resulted in an increased basal activity of MSK1, but this could be further increased by stimulation with PMA or UV-C radiation. Surprisingly, however, mutation of Thr 700 resulted in a dramatic loss of Thr 581 phosphorylation, a site essential for activity. Mutation of Thr 700 and Thr 581 to an alanine residue resulted in an inactive kinase, while mutation of both sites to an aspartic acid residue resulted in a kinase with a significant basal activity that could not be further stimulated. Together these results are consistent with a mechanism by which Thr 700 phosphorylation relieves the inhibition of MSK1 by a C-terminal autoinhibitory helix and helps induce a conformational shift that protects Thr 581 from dephosphorylation.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 52%

Identification of novel phosphorylation sites in MSK1 by precursor ion scanning MS

McCoy

Macdonald

Morrice

et al. 2007

Biochemical Journal

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“…2). This docking sequence is necessary for ERK1/2 docking to RSKs (62,165,189) and MNK2B (170), ERK1/2 and p38 binding to MSK2 (207), as well as p38 docking to MK5 (179). It is likely that MAPK docking specificity arises from variations in the D domain sequence and from the potential involvement of other unidentified regions within the MKs.…”

Section: Docking Interactions With Mksmentioning

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

2,158

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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“…Moreover Ser 742 appears to be phosphorylated by the activated NTK (28,36), which results in decreased affinity of RSK for ERK, serving as an intramolecular feedback inhibitory mechanism that operates in RSK1 and RSK2 but not in RSK3 (36). The activation mechanism of MSK is thought to be very similar to that of RSK except for two features (22,23,(37)(38)(39). First, the MAP kinase docking site can interact with both ERK and p38 MAP kinase, explaining why MSK is activated by two MAP kinase pathways.…”

mentioning

confidence: 99%

Functional Characterization of Human RSK4, a New 90-kDa Ribosomal S6 Kinase, Reveals Constitutive Activation in Most Cell Types

Dümmler

Hauge

Silber

et al. 2005

Journal of Biological Chemistry

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The 90-kDa ribosomal S6 kinases (RSK1-3) are important mediators of growth factor stimulation of cellular proliferation, survival, and differentiation and are activated via coordinated phosphorylation by ERK and 3-phosphoinositide-dependent protein kinase-1 (PDK1). Here we performed the functional characterization of a predicted new human RSK homologue, RSK4. We showed that RSK4 is a predominantly cytosolic protein with very low expression and several characteristics of the RSK family kinases, including the presence of two functional kinase domains and a C-terminal docking site for ERK. Surprisingly, however, in all cell types analyzed, endogenous RSK4 was maximally ( cdc2 -inhibitory kinase Myt1 (7) and the protein kinase Bub1 (8), respectively. In somatic cell types, RSK may stimulate cell division through phosphorylation of substrates like p27 Kip1 (9) and glycogen synthase kinase-3 (10 -12); protein synthesis and cell growth through substrates like elongation factor 2 kinase (13), glycogen synthase kinase-3 (10 -12), transcription initiation factor IA (14), and tuberous sclerosis complex-2 protein (15); cell survival through Bad (16); and transcription through substrates like c-Fos (17) and estrogen receptor (18). Experiments with PC12 cells suggest that RSK is a key mediator of ERK in neurotrophin-induced neuronal differentiation (19). Finally genetic evidence from human and mouse has identified an important role for RSK2 in osteoblast differentiation and function through phosphorylation of activating transcription factor-4 (20) and in stimulation of white adipose tissue mass via an unknown mechanism (21). RSK is related to the mitogen-and stress-activated protein kinases (MSK1 and MSK2), which also contain two kinase domains. MSK, however, is activated by the ERK family as well as by p38 family MAP kinases and thereby functions in signal transduction of growth factors as well as of cellular stress stimuli like UV/radioactive irradiation and proinflammatory cytokines (22,23).The substrates of RSK are phosphorylated by the N-terminal kinase (NTK) domain (24 -27) whose activity is regulated by

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

Cited by 28 publications

References 46 publications

Identification of novel phosphorylation sites in MSK1 by precursor ion scanning MS

Identification of novel phosphorylation sites in MSK1 by precursor ion scanning MS

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

Functional Characterization of Human RSK4, a New 90-kDa Ribosomal S6 Kinase, Reveals Constitutive Activation in Most Cell Types

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