ERK activation induces phosphorylation of Elk-1 at multiple S/T-P motifs to high stoichiometry

Cruzalegui, Francisco; Cano, Eva; Treisman, Richard

doi:10.1038/sj.onc.1203362

Cited by 162 publications

(121 citation statements)

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“…For example, activation of ERK1/2 leads to the coordinated stimulation of c-fos expression by acting on transcription factors bound at the c-fos promoter, such as Elk-1 that is also known as ternary complex factor (TCF) (Whitmarsh et al, 1995), and by the subsequent post-translational modification of c-Fos by the direct multisite phosphorylation of the c-Fos TAD that greatly enhances c-Fos activity and stability (Murphy et al, 2002;Monje et al, 2003). On the other hand, Elk-1 is one of the best-studied targets of the ERK cascade, as ERKs phosphorylate Elk-1 in several sites thereby increasing its transcriptional activity (Gille et al, 1992;Cruzalegui et al, 1999).…”

Section: Mapkmentioning

confidence: 99%

“…These sites are recognized by prolyl isomerases, such as Pin, which can accelerate the changes in the conformation of the phosphorylated Ser/Thr residues therefore modulating the activity of transcription factors (Monje et al, 2005;Wulf et al, 2005). In addition, in several cases the targets of MAPKs have multi phosphorylation sites, which may act in a synergistic fashion to promote gene expression (Smeal et al, 1991;Cruzalegui et al, 1999;Monje et al, 2003;Tanos et al, 2005). On the other hand, although less frequent, MAPKs can also inhibit the activity of transcription factors, for example by promoting their retention in the cytoplasm upon phosphorylation.…”

Section: Signaling To the Nucleus Through Mapksmentioning

confidence: 99%

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MAP kinases and the control of nuclear events

2007

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The mitogen-activated protein kinases (MAPKs) are a family of serine/threonine kinases that play an essential role in signal transduction by modulating gene transcription in the nucleus in response to changes in the cellular environment. They include the extracellular signal-regulated protein kinases (ERK1 and ERK2); c-Jun N-terminal kinases (JNK1, JNK2, JNK3); p38s (p38a, p38b, p38c, p38d) and ERK5. The molecular events in which MAPKs function can be separated in discrete and yet interrelated steps: activation of the MAPK by their upstream kinases, changes in the subcellular localization of MAPKs, and recognition, binding and phosphorylation of MAPK downstream targets. The resulting pattern of gene expression will ultimately depend on the integration of the combinatorial signals provided by the temporal activation of each group of MAPKs. This review will focus on how the specificity of signal transmission by MAPKs is achieved by scaffolding molecules and by the presence of structural motifs in MAPKs that are dynamically regulated by phosphorylation and protein-protein interactions. We discuss also how MAPKs recognize and phosphorylate their target nuclear proteins, including transcription factors, co-activators and repressors and chromatin-remodeling molecules, thereby affecting an intricate balance of nuclear regulatory molecules that ultimately control gene expression in response to environmental cues.

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Section: Mapkmentioning

confidence: 99%

Section: Signaling To the Nucleus Through Mapksmentioning

confidence: 99%

MAP kinases and the control of nuclear events

2007

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“…The reduction in cell proliferation is most likely ultimately due to modulation of transcription of genes that encode cell cycle proteins by transcription factors that are phosphorylated by ERK. For example, ERK can phosphorylate Elk1 (16,17), which then regulates the transcription of c-fos. Moreover, when inactivation of ERK is delayed, direct phosphorylation of c-fos by ERK stabilizes fos protein (18).…”

Section: Azd6244 An Inhibitor Of Mek1/2 Kinasesmentioning

confidence: 99%

AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models

Davies

Logié

McKay³

et al. 2007

Molecular Cancer Therapeutics

371

347

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Constitutive activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway in human cancers is often associated with mutational activation of BRAF or RAS. MAPK/ERK kinase 1/2 kinases lie downstream of RAS and BRAF and are the only acknowledged activators of ERK1/ 2, making them attractive targets for therapeutic intervention. AZD6244 (ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of MAPK/ERK kinase 1/2. In vitro cell viability inhibition screening of a tumor cell line panel found that lines harboring BRAF or RAS mutations were more likely to be sensitive to AZD6244. The in vivo mechanisms by which AZD6244 inhibits tumor growth were investigated. Chronic dosing with 25 mg/kg AZD6244 bd resulted in suppression of growth of Colo-205, Calu-6, and SW-620 xenografts, whereas an acute dose resulted in significant inhibition of ERK1/2 phosphorylation. Increased cleaved caspase-3, a marker of apoptosis, was detected in Colo-205 and Calu-6 but not in SW-620 tumors where a significant decrease in cell proliferation was detected. Chronic dosing of AZD6244 induced a morphologic change in SW-620 tumors to a more differentiated phenotype. The potential of AZD6244 in combination with cytotoxic drugs was evaluated in mice bearing SW-620 xenografts. Treatment with tolerated doses of AZD6244 and either irinotecan or docetaxel resulted in significantly enhanced antitumor efficacy relative to that of either agent alone. These results indicate that AZD6244 has potential to inhibit proliferation and induce apoptosis and differentiation, but the response varies between different xenografts. Moreover, enhanced antitumor efficacy can be obtained by combining AZD6244 with the cytotoxic drugs irinotecan or docetaxel.

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“…1A; fig. S1) (6)(7)(8)(9)(10)(11). Two MAP kinase-docking sites, the D-box and the Phe-Gln-Phe-Pro (FQFP) motif, control phosphorylation of these sites (12)(13)(14)(15).…”

mentioning

confidence: 99%

Opposing effects of Elk-1 multisite phosphorylation shape its response to ERK activation

Mylona

Theillet

Foster

et al. 2016

Science

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112

132

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Multisite phosphorylation regulates many transcription factors, including the Serum Response Factor partner Elk-1. Phosphorylation of the transcriptional activation domain (TAD) of Elk-1 by the protein kinase ERK at multiple sites potentiates recruitment of the Mediator transcriptional coactivator complex and transcriptional activation, but the roles of individual phosphorylation events remained unclear. Using time-resolved nuclear magnetic resonance spectroscopy, we found that ERK2 phosphorylation proceeds at markedly different rates at eight TAD sites in vitro, which we classified as fast, intermediate and slow. Mutagenesis experiments showed that phosphorylation of fast and intermediate sites promoted Mediator interaction and transcriptional activation, whereas modification of slow sites counteracted both functions, thereby limiting Elk-1 output. Progressive Elk-1 phosphorylation thus ensures a self-limiting response to ERK activation, which occurs independently of antagonizing phosphatase activity. Results and DiscussionMultisite protein phosphorylation increases the complexity of functional signaling outputs that can be generated from single protein kinase inputs. It can set thresholds for activity, or transform graded signals into switch-like responses (1-4). Many transcription factors and their interacting regulatory proteins are subject to multisite phosphorylation, which allows distinct aspects of protein function, including protein turnover, nuclear import and export, and specific protein interactions, to be controlled independently (5). However, in general, the † The ternary complex factor (TCF) subfamily of Ets-domain transcription factors, consisting of Elk-1, SAP-1, and Net, provides an example of multisite phosphorylation in transcriptional activation. TCFs, together with their partner protein SRF, function in many biological processes by coupling SRF target genes to mitogen-activated protein kinase (MAP kinase) signaling (5). Mitogenic and stress stimuli induce phosphorylation of TCF Cterminal transcriptional activation domains (TADs) at multiple S/T-P (Ser-or Thr-Pro) phosphorylation sequences, of which eight are conserved across the family ( Fig. 1A; fig. S1) (6-11). Two MAP kinase-docking sites, the D-box and the Phe-Gln-Phe-Pro (FQFP) motif, control phosphorylation of these sites (12-15). Multisite phosphorylation triggers transcriptional activation by TCFs, facilitating their interaction with the Mediator transcriptional co-activator complex (16-19) but the kinetics with which the different sites are phosphorylated, and whether they serve distinct functions, remain unclear.To obtain atomic-resolution insights into phosphorylation of the Elk-1 TAD, we used nuclear magnetic resonance (NMR) spectroscopy (20) Fig. 2A). In the fast site mutant Elk-1F, phosphorylation rates of intermediate and slow sites increased, whereas those of the fast and slow sites increased in the intermediate-site mutant Elk-1I; in both cases the altered kinetics fit well with those predicted by the model (Fig 2B,...

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ERK activation induces phosphorylation of Elk-1 at multiple S/T-P motifs to high stoichiometry

Cited by 162 publications

References 36 publications

MAP kinases and the control of nuclear events

MAP kinases and the control of nuclear events

AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models

Opposing effects of Elk-1 multisite phosphorylation shape its response to ERK activation

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