MSK1 activity is controlled by multiple phosphorylation sites

McCoy, Claire E.; Campbell, David G.; Deák, Mária; Bloomberg, Graham B.; Arthur, J. Simon C.

doi:10.1042/bj20041501

Cited by 146 publications

(188 citation statements)

References 38 publications

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“…Therefore, the inhibition of the activation loop phosphorylation of MSK1/2 by 3,4-DMB-PP1 or 1-NM-PP1 is likely a secondary event due to non-specific inhibition of the priming site phosphorylation. These results therefore indicate that phosphorylation of the Nterminal kinase domain activation loop site in MSK1 occurs independently of PDK1, which is consistent with previous observations [16,33].…”

Section: Phosphorylation Of Known and Potential Pdk1 Targets Followinsupporting

confidence: 93%

Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells

Tamgüney

Zhang

Fiedler

et al. 2008

Experimental Cell Research

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Abstract3-Phosphoinositide-dependent kinase-1 (PDK1) phosphorylates and activates several kinases in the cAMP-dependent, cGMP-dependent and protein kinase C(AGC) family. Many putative PDK1 substrates have been identified, but have not been analyzed following transient and specific inhibition of PDK1 activity. Here, we demonstrate that a previously characterized PDK1 inhibitor, BX-795, shows biological effects that are not consistent with PDK1 inhibition. Therefore, we describe the creation and characterization of a PDK1 mutant, L159G, which can bind inhibitor analogues containing bulky groups that hinder access to the ATP binding pocket of wild type (WT) kinases. When expressed in PDK1 −/− ES cells, PDK1 L159G restored phosphorylation of PDK1 targets known to be hypophosphorylated in these cells. Screening of multiple inhibitor analogues showed that 1-NM-PP1 and 3,4-DMB-PP1 optimally inhibited the phosphorylation of PDK1 targets in PDK1 −/− ES cells expressing PDK1 L159G but not WT PDK1. These compounds confirmed previously assumed PDK1 substrates, but revealed distinct dephosphorylation kinetics. While PDK1 inhibition had little effect on cell growth, it sensitized cells to apoptotic stimuli. Furthermore, PDK1 loss abolished growth of allograft tumors. Taken together we describe a model system that allows for acute and reversible inhibition of PDK1 in cells, to probe biochemical and biological consequences.

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Section: Phosphorylation Of Known and Potential Pdk1 Targets Followinsupporting

confidence: 93%

Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells

Tamgüney

Zhang

Fiedler

et al. 2008

Experimental Cell Research

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“…Two of the peaks corresponded to residues 371-385 of MSK1 that had been phosphorylated on Ser 376 or on both Ser 376 and Ser 381 ( Figure 1, peaks 1 and 2). These sites had been previously identified as sites phosphorylated by the C-terminal kinase domain [24]. A peptide corresponding to 210-226 of MSK1 that was phosphorylated on Ser 212 , another site phosphorylated by the C-terminal kinase domain, was also identified in this analysis ( Figure 1, peak 3).…”

Section: Analysis Of Msk1 Phosphorylation By Precursor Ion Scanning Msmentioning

confidence: 73%

“…MSK1 antibodies against phospho-Ser 360 , phospho-Ser 376 and phospho-Thr 581 were from Cell Signaling Technology, while the phospho-Ser 212 , phospho-Ser 381 phospho-Ser 750 and dually phosphorylated Ser 750/752 and GST antibodies have been described previously [24]. FLAG antibody was from Sigma.…”

Section: Antibodiesmentioning

confidence: 99%

“…Phosphorylation of MSK1 by ERK1/2 or p38 was found to activate the C-terminal kinase domain, which then autophosphorylates two sites in the linker region (Ser 376 and Ser 381 ) and a site in the T-loop of the N-terminal kinase domain (Ser 212 ). Of these three sites, Ser 212 and Ser 376 appear to be essential for MSK activation as their mutation, to alanine prevents MSK1 activation [24]. These autophosphorylation events activate the Nterminal kinase domain, allowing the phosphorylation of three sites in the C-terminus of MSK1 (Ser 750 , Ser 752 and Ser 758 ), as well as the phosphorylation of MSK substrates such as CREB and ATF1.…”

Section: Introductionmentioning

confidence: 99%

“…One site was in the activation loop of the C-terminal kinase domain (Thr 581 in human MSK1), while the other (Ser 360 ) was in the linker region between the two domains. Subsequent work has shown that mutagenesis of these sites in MSK1 and MSK2 prevents the full activation of MSK, and these sites have been shown to be phosphorylated in cells by ERK1/2 or p38 [24,25]. Phosphorylation of MSK1 by ERK1/2 or p38 was found to activate the C-terminal kinase domain, which then autophosphorylates two sites in the linker region (Ser 376 and Ser 381 ) and a site in the T-loop of the N-terminal kinase domain (Ser 212 ).…”

Section: Introductionmentioning

confidence: 99%

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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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MSK1 regulates transcriptional induction of Arc/Arg3.1 in response to neurotrophins

et al. 2017

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The immediate early gene activity‐regulated cytoskeletal protein (Arc)/Arg3.1 and the neurotrophin brain‐derived neurotrophic factor (BDNF) play important roles in synaptic plasticity and learning and memory in the mammalian brain. However, the mechanisms by which BDNF regulates the expression of Arc/Arg3.1 are unclear. In this study, we show that BDNF acts via the ERK1/2 pathway to activate the nuclear kinase mitogen‐ and stress‐activated protein kinase 1 (MSK1). MSK1 then induces Arc/Arg3.1 expression via the phosphorylation of histone H3 at the Arc/Arg3.1 promoter. MSK1 can also phosphorylate the transcription factor cyclic‐AMP response element‐binding protein (CREB) on Ser133. However, this is not required for BDNF‐induced Arc.Arg3.1 transcription as a Ser133Ala knockin mutation had no effect on Arc/Arg3.1 induction. In parallel, ERK1/2 directly activates Arc/Arg3.1 mRNA transcription via at least one serum response element on the promoter, which bind a complex of the Serum Response Factor (SRF) and a Ternary Complex Factor (TCF).

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MSK1 activity is controlled by multiple phosphorylation sites

Cited by 146 publications

References 38 publications

Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells

Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells

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

MSK1 regulates transcriptional induction of Arc/Arg3.1 in response to neurotrophins

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