Extracellular-Regulated Kinases: Signaling From Ras to ERK Substrates to Control Biological Outcomes

Eblen, Scott T.

doi:10.1016/bs.acr.2018.02.004

Cited by 151 publications

(114 citation statements)

References 209 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…(i) Extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is composed mainly of Raf (usually B and C isoforms), MEK1/2, ERK1/2 and several MAPKAPKs. The main function of this cascade is the regulation of proliferation and differentiation [5, 6]. (ii) cJun-N-terminal kinase (JNK) 1–3 (JNKs) cascade is usually composed of various kinases in the upper 2 layers of the cascade (MAP4K and MAP3K), which further transmit the signal to MKK4/7 and further to JNK1–3.…”

Section: Overview Of the Composition And Regulation Of The Mitogen-acmentioning

confidence: 99%

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

et al. 2018

View full text Add to dashboard Cite

The mitogen-activated protein kinase (MAPK) cascades are central signaling pathways that play a central role in the regulation of most stimulated cellular processes including proliferation, differentiation, stress response and apoptosis. Currently 4 such cascades are known, each termed by its downstream MAPK components: the extracellular signal-regulated kinase 1/2 (ERK1/2), cJun-N-terminal kinase (JNK), p38 and ERK5. One of the hallmarks of these cascades is the stimulated nuclear translocation of their MAPK components using distinct mechanisms. ERK1/2 are shuttled into the nucleus by importin7, JNK and p38 by a dimer of importin3 with either importin9 or importin7, and ERK5 by importin-α/β. Dysregulation of these cascades often results in diseases, including cancer and inflammation, as well as developmental and neurological disorders. Much effort has been invested over the years in developing inhibitors to the MAPK cascades to combat these diseases. Although some inhibitors are already in clinical use or clinical trials, their effects are hampered by development of resistance or adverse side-effects. Recently, our group developed 2 myristoylated peptides: EPE peptide, which inhibits the interaction of ERK1/2 with importin7, and PERY peptide, which prevents JNK/p38 interaction with either importin7 or importin9. These peptides block the nuclear translocation of their corresponding kinases, resulting in prevention of several cancers, while the PERY peptide also inhibits inflammation-induced diseases. These peptides provide a proof of concept for the use of the nuclear translocation of MAPKs as therapeutic targets for cancer and/or inflammation.

show abstract

Section: Overview Of the Composition And Regulation Of The Mitogen-acmentioning

confidence: 99%

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Upon ligand binding, RTKs undergo autophosphorylation and then recruit and activate RAS, which in turn phosphorylates RAFs [4]. The signal is then transduced to MEK1/2, followed by ERK1/2, which consecutively regulates their many substrates involved in substantial cell functions like proliferation or migration [5]. The majority of BRAF mutations occur in exon 15 Int.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment

Dratkiewicz

Simiczyjew

Pietraszek-Gremplewicz

et al. 2019

IJMS

View full text Add to dashboard Cite

Constitutively active mutated BRAF kinase occurs in more than 40% of patients suffering from melanoma. To block its activity, a specific inhibitor, vemurafenib, is applied as a therapy. Unfortunately, patients develop resistance to this drug rather quickly. Previously, we demonstrated that pairs of inhibitors directed against EGFR (epidermal growth factor receptor) and MET (hepatocyte growth factor receptor) trigger a synergistic cytotoxic effect in human melanoma cells, and decrease their invasive abilities. In this study, we aimed to generate and characterize melanoma cells resistant to vemurafenib treatment, and then to evaluate the effectiveness of a previously developed therapy in this model. We showed that melanoma cells resistant to the BRAF inhibitor are characterized by a lower proliferation rate and they acquire a spindle-like shape. Using Western Blot, we also noticed increased levels of EGFR, MET, and selected markers of cancer stem cells in generated cell lines. Resistant cells also exhibited increased invasive abilities and elevated proteolytic activity, observed using scratch wound assays and gelatin zymography. Moreover, combination therapy reduced their viability, as measured with a colorimetric cytotoxicity test, and decreased invasiveness. The obtained results validate the application of combination therapy directed against EGFR and MET in melanoma cells resistant to treatment with inhibitors of mutated BRAF.

show abstract

“…On one hand, the use of MEK inhibitors can only demonstrate a permissive for the pathway role (“is ERK signalling necessary?”) but precludes any investigation of the potential instructive role (“is ERK signalling sufficient?”). On the other hand, genetic models selectively alter the expression of a key component of the pathway either early in development (global gene manipulation) or for a prolonged period of time (weeks to months, in case of tissue/cell specific gene targeting) whose effects maybe confounded by associated cellular adaptations and compensatory mechanisms 35,36 .…”

Section: Discussionmentioning

confidence: 99%

Modulation of ERK1/MAPK3 potentiates ERK nuclear signalling, facilitates neuronal cell survival and improves memory in mouse models of neurodegenerative disorders

Indrigo

Morella

Orellana

et al. 2018

Preprint

View full text Add to dashboard Cite

Cell signalling mechanisms are central to neuronal activity and their dysregulation may lead to neurodegenerative processes and associated cognitive decline. So far, a major effort has been directed toward the dissection of disease specific pathways with the still unmet promise to develop precision medicine strategies. With a different approach, here we show that a selective genetic potentiation of neuronal ERK signalling prevents cell death in vitro and in vivo in the mouse brain while ERK attenuation does the opposite. This neuroprotective effect can also be induced pharmacologically by a cell permeable peptide mimicking the loss of ERK1 MAP kinase, leading to a selective enhancement of ERK2 mediated nuclear cell signalling. The drug treatment prevents neurodegeneration in mouse models of Huntington’s (HD), Alzheimer’s (AD), and Parkinson’s disease (PD). Importantly, the selective potentiation of ERK2 signalling facilitates both structural and synaptic plasticity, enhances cognition in healthy mice and rescues mild cognitive impairments in both models of AD and HD. Altogether, our observation truly represents a remarkable example of a shared molecular mechanism across multiple neurodegenerative disorders and a potentially valuable therapeutic target for neuro-enhancement.

show abstract

Extracellular-Regulated Kinases: Signaling From Ras to ERK Substrates to Control Biological Outcomes

Cited by 151 publications

References 209 publications

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment

Modulation of ERK1/MAPK3 potentiates ERK nuclear signalling, facilitates neuronal cell survival and improves memory in mouse models of neurodegenerative disorders

Contact Info

Product

Resources

About