Intrinsically active variants of Erk oncogenically transform cells and disclose unexpected autophosphorylation capability that is independent of TEY phosphorylation

Smorodinsky-Atias, Karina; Goshen-Lago, Tal; Goldberg-Carp, Anat; Melamed, Dganit; Shir, Alexei; Mooshayef, Navit; Beenstock, Jonah; Karamansha, Y.; Darlyuk-Saadon, Ilona; Livnah, Oded; Ahn, Natalie G.; Admon, Arie; Engelberg, David

doi:10.1091/mbc.e15-07-0521

Cited by 40 publications

(62 citation statements)

References 66 publications

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“…A number of catalytically active ERK2 mutants have been previously identified (Bott et al, 1994; Chu et al, 1996; Emrick et al, 2001; Emrick et al, 2006; Goetz et al, 2014; Levin-Salomon et al, 2008; Levin-Salomon et al, 2009; Robinson et al, 1998; Shin et al, 2010; Smorodinsky-Atias et al, 2016) (Table S2). However, the identification of tumor-associated ERK2 mutants with GOF in-cell phenotypes has remained elusive in spite of the prevalence of constitutively active oncogenic missense mutants in upstream pathway members, including Ras-family members, BRAF and MEK1/2 that signal through ERK1/2 (Roskoski, 2012).…”

Section: Resultsmentioning

confidence: 99%

Phenotypic Characterization of a Comprehensive Set of MAPK1 /ERK2 Missense Mutants

et al. 2016

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SUMMARY Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1/ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain- and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants. Gain-of-function ERK2 mutants induced variable responses to RAF-, MEK- and ERK-directed therapies, providing a reference for future treatment decisions. Tumor-associated mutations spatially clustered in two ERK2 effector-recruitment domains, yet produced mutants with opposite phenotypes. This approach articulates an allele-characterization framework that can be scaled to meet the goals of genome-guided oncology.

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Section: Resultsmentioning

confidence: 99%

Phenotypic Characterization of a Comprehensive Set of MAPK1 /ERK2 Missense Mutants

et al. 2016

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“…However, strong down-regulation of β-actin blocks G2/M phase and cell cycle progression, reducing late cyclins. ERK1/2 activation throughout G1 is required for cell proliferation to proceed [33,34], especially as direct activation of ERK1/2 leads to its oncogenic role [35].…”

Section: Discussionmentioning

confidence: 99%

Divergent impact of actin isoforms on cell cycle regulation

et al. 2018

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We have shown that cytoplasmic actin isoforms play different roles in neoplastic cell transformation. β-Cytoplasmic actin acts as a tumor suppressor, affecting epithelial differentiation, cell growth, cell invasion and tumor growth of colon and lung carcinoma cells. In contrast, γ-cytoplasmic actin enhances malignant features of tumor cells whose actin network regulation is carried out via the γ-actin isoform. The goal of this study was to describe the role of cytoplasmic actins in cell cycle regulation of breast cancer cell lines MCF-7 and MDA-MB-231. The distinct roles of each cytoplasmic actin in the cell cycle driving were observed. β-Actin as well as γ-actin down-regulation inhibited proliferation of breast cancer cells, but only down-regulation of β-actin induced a significant decrease in diploid cell population and accumulation of tetraploid cells. Down-regulation of β-actin stimulated cyclin A2, B1 and D3 expression, whereas down-regulation of γ-actin reduced expression of these cyclins in both cell lines. Moreover, cyclin B1 and γ-actin were co-localized in mitotic control and β-actin-deficient cells. In mitotic MCF-7 cells down-regulation of β-actin caused an enrichment of prophase/metaphase population compared with control. γ-Actin down-regulation induced telophase enrichment.ERK1/2 and γ-actin co-localization and possible selective binding were revealed in MCF7 cells. β-Actin down-regulation induced ERK1/2 activation, while γ-actin down-regulation led to reduction of p-ERK1/2. A direct interaction of ERK1/2 with γ-actin and cyclin A2 in the same protein complex was also discovered. We suggest that γ-actin down-regulation leads to decrease of cyclin A2 level, inhibits ERK1/2 signaling and deceleration of breast cancer cells proliferation.

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“…Indeed, activating mutations of components of the ERK1/2 cascade (Raf, MEK, ERK1/2) and their immediate upstream activator Ras are the cause of 35–40% of all cancer types [86], and are responsible for more than 10% of all cancer cases [87]. MEK mutations are found only in a few cancers [88-90] and are responsible for ∼1% of cases, while ERK1/2 mutations are rare [91, 92]. MOS and COT upstream of MEK can serve as oncogenes as well, but their prevalence is very low.…”

Section: Mapk Cascades In Diseasementioning

confidence: 99%

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

et al. 2018

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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.

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Intrinsically active variants of Erk oncogenically transform cells and disclose unexpected autophosphorylation capability that is independent of TEY phosphorylation

Cited by 40 publications

References 66 publications

Phenotypic Characterization of a Comprehensive Set of MAPK1 /ERK2 Missense Mutants

Phenotypic Characterization of a Comprehensive Set of MAPK1 /ERK2 Missense Mutants

Divergent impact of actin isoforms on cell cycle regulation

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

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