ERK1/2 can feedback-regulate cellular MEK1/2 levels

Hong, Seung–Keun; Wu, Pui Kei; Karkhanis, Mansi; Park, Jong In

doi:10.1016/j.cellsig.2015.07.003

Cited by 22 publications

(26 citation statements)

References 43 publications

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“…Moreover, we previously demonstrated that although MEK1 levels are mildly upregulated under conditions of mortalin depletion (Fig. 6, bottom panel), this is mainly due to MEK1 transcription upregulated via an ERK1/2-mediated feedback loop, which is activated by mortalin depletion (48). Of note, a recent report has demonstrated that HSP70 can also regulate the stability of folded proteins via a mechanism wherein its lid and substrate- , and PP1␥ in melanoma and pancreatic ductal adenocarcinoma patient biopsy specimens determined by the copy number analysis algorithms defined by genomic identification of significant targets in cancer (GISTIC) (63) and RAE (64).…”

Section: Discussionmentioning

confidence: 99%

Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells

Hong

Park

2017

Molecular and Cellular Biology

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Although deregulation of MEK/extracellular signal-regulated kinase (ERK) activity is a key feature in cancer, high-magnitude MEK/ERK activity can paradoxically induce growth inhibition. Therefore, additional mechanisms may exist to modulate MEK/ERK activity in favor of tumor cell proliferation. We previously reported that mortalin/HSPA9 can facilitate proliferation of certain KRAS and BRAF tumor cells by modulating MEK/ERK activity. In this study, we demonstrated that mortalin can regulate MEK/ERK activity via protein phosphatase 1␣ (PP1␣). We found that PP1␣ inhibition increases steady-state levels of phosphorylated MEK1/2 in various tumor cells expressing B-Raf V600E or K-Ras G12C/D . Intriguingly, coimmunoprecipitation and in vitro binding assays revealed that mortalin facilitates PP1␣-mediated MEK1/2 dephosphorylation by promoting PP1␣-MEK1/2 interaction in an ATP-sensitive manner. The region spanning Val482 to Glu491 in the substrate-binding cavity and the substrate lid of mortalin were necessary for these physical interactions, which is consistent with conventional heat shock protein 70 (HSP70)-client interaction mechanisms. Nevertheless, mortalin depletion did not affect cellular PP1␣ levels or its regulatory phosphorylation, suggesting a nonconventional role for mortalin in promoting PP1␣-MEK1/2 interaction. Of note, PP1␣ was upregulated in human melanoma and pancreatic cancer biopsy specimens in correlation with mortalin upregulation. PP1␣ may therefore have a role in tumorigenesis in concert with mortalin, which affects MEK/ERK activity in tumor cells. KEYWORDS MEK1/2, ERK1/2, protein phosphatase 1, heat shock protein, mortalin T he Raf/MEK/extracellular signal-regulated kinase (ERK) pathway is a highly specific three-layer kinase cascade that consists of the Ser/Thr kinases, Raf (i.e., A-, B-, and C-Raf), the highly homologous dual-specificity kinases MEK1 and MEK2 (collectively referred to as MEK1/2), and the ubiquitously expressed Ser/Thr kinases ERK1/2 (1). Upon activation, Raf phosphorylates two Ser residues in the activation segment of MEK1/2, which in turn activate ERK1/2 by sequentially phosphorylating Tyr and Thr in their activation loop (2). ERK1/2 then activate/inactivate various targets, including transcription factors, other kinases, phosphatases, cytoskeletal proteins, scaffolds, receptors, and signaling components (1). The Raf/MEK/ERK pathway has pivotal roles in regulating cell survival, cell cycle progression, and differentiation (3), and its deregulation often leads to the onset of cancer, including malignancies of skin, thyroid, pancreas, and colon, wherein mutations in BRAF and its upstream activator, RAS, are prevalent (4).Diverse physiological outputs of Raf/MEK/ERK signaling are determined by the duration and strength of signals, physical interactions with specific scaffolds, subcellular compartmentalization, cross talk with other signaling pathways, and distinct functions

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Section: Discussionmentioning

confidence: 99%

Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells

Hong

Park

2017

Molecular and Cellular Biology

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“…ERK phosphorylates numerous substrates in the cytoplasm and nucleus that play a role in cell fate, such as RSK and the AP‐1 and ETS families of transcription factors. (B) The ERK pathway has many intrinsic mechanisms of negative feedback regulation . ERK can exert negative feedback at each level of the pathway via phosphoregulation.…”

Section: Overview Of the Erk Signaling Pathwaymentioning

confidence: 99%

“…ERK can exert negative feedback at each level of the pathway via phosphoregulation. ERK can also drive transcription of negative pathway regulators such as DUSP5/6 and SPRY that can and inactivate members of the ERK pathway . Abbreviations: AP‐1, activating protein‐1; ERK, extracellular signal‐regulated kinase; DUSP, dual specificity phosphatase; Grb, growth factor receptor‐bound protein; MEK, mitogen‐activated protein kinase/ERK kinase; RSK, ribosomal s6 kinase; RTK, receptor tyrosine kinase; SOS, Son of Sevenless homolog; SPRY, sprouty homolog [Color figure can be viewed at wileyonlinelibrary.com]…”

Section: Overview Of the Erk Signaling Pathwaymentioning

confidence: 99%

“…One of the ways this is achieved is through negative feedback within the ERK pathway, some examples of which are illustrated in Figure B. ERK can directly phosphorylate and inhibit upstream pathway components such as Raf, Sos, and some receptor tyrosine kinases, and ERK signaling can also differentially regulate MEK1/2 levels . Additionally, ERK phosphorylates transcription factors that induce expression of negative regulators of the ERK pathway, such as dual specificity phosphatases 5/6 (DUSP5/6) and sprouty homolog (SPRY) .…”

Section: Overview Of the Erk Signaling Pathwaymentioning

confidence: 99%

“…ERK can directly phosphorylate and inhibit upstream pathway components such as Raf, Sos, and some receptor tyrosine kinases, and ERK signaling can also differentially regulate MEK1/2 levels. [10][11][12] Additionally, ERK phosphorylates transcription factors that induce expression of negative regulators of the ERK pathway, such as dual specificity phosphatases 5/6 (DUSP5/6) and sprouty homolog (SPRY). 13,14 Therefore, ERK activity itself can, directly and indirectly, F I G U R E 1 ERK phosphorylation cascade and feedback signaling.…”

Section: Pathway Feedbackmentioning

confidence: 99%

See 2 more Smart Citations

Targeting ERK beyond the boundaries of the kinase active site in melanoma

Sammons

Ghose

Tsai

et al. 2019

Molecular Carcinogenesis

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Extracellular signal‐regulated kinase 1/2 (ERK1/2) constitute a point of convergence for complex signaling events that regulate essential cellular processes, including proliferation and survival. As such, dysregulation of the ERK signaling pathway is prevalent in many cancers. In the case of BRAF‐V600E mutant melanoma, ERK inhibition has emerged as a viable clinical approach to abrogate signaling through the ERK pathway, even in cases where MEK and Raf inhibitor treatments fail to induce tumor regression due to resistance mechanisms. Several ERK inhibitors that target the active site of ERK have reached clinical trials, however, many critical ERK interactions occur at other potentially druggable sites on the protein. Here we discuss the role of ERK signaling in cell fate, in driving melanoma, and in resistance mechanisms to current BRAF‐V600E melanoma treatments. We explore targeting ERK via a distinct site of protein‐protein interaction, known as the D‐recruitment site (DRS), as an alternative or supplementary mode of ERK pathway inhibition in BRAF‐V600E melanoma. Targeting the DRS with inhibitors in melanoma has the potential to not only disrupt the catalytic apparatus of ERK but also its noncatalytic functions, which have significant impacts on spatiotemporal signaling dynamics and cell fate.

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Transcriptional Response of White Adipose Tissue to Withdrawal of Vitamin B3

Shi

Hegeman

Doncheva

et al. 2019

Molecular Nutrition Food Res

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Scope Distinct markers for mild vitamin B3 deficiency are lacking. To identify these, the molecular responses of white adipose tissue (WAT) to vitamin B3 withdrawal are examined. Methods and results A dietary intervention is performed in male C57BL/6JRccHsd mice, in which a diet without nicotinamide riboside (NR) is compared to a diet with NR at the recommended vitamin B3 level. Both diets contain low but adequate level of tryptophan. Metabolic flexibility and systemic glucose tolerance are analyzed and global transcriptomics, qRT‐PCR, and histology of epididymal WAT (eWAT) are performed. A decreased insulin sensitivity and a shift from carbohydrate to fatty acid oxidation in response to vitamin B3 withdrawal are observed. This is consistent with molecular changes in eWAT, including an activated MEK/ERK signaling, a lowering of glucose utilization markers, and an increase in makers of fatty acid catabolism, possibly related to the consistent lower expression of mitochondrial electron transport complexes. The synthesis pathway of tetrahydropteridine (BH4), an essential cofactor for neurotransmitter synthesis, is transcriptionally activated. Genes marking these processes are technically validated. Conclusion The downregulation of Anp32a , Tnk2 and the upregulation of Mapk1 , Map2k1 , Qdpr , Mthfs , and Mthfsl are proposed as a WAT transcriptional signature marker for mild vitamin B3 deficiency.

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ERK1/2 can feedback-regulate cellular MEK1/2 levels

Cited by 22 publications

References 43 publications

Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells

Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells

Targeting ERK beyond the boundaries of the kinase active site in melanoma

Transcriptional Response of White Adipose Tissue to Withdrawal of Vitamin B3

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