Targeting the ERK signaling pathway in cancer therapy

Kohno, Michiaki; Pouysségur, Jacques

doi:10.1080/07853890600551037

Cited by 357 publications

(293 citation statements)

References 58 publications

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“…The ERK signaling pathway is a major determinant in the control of diverse cellular processes, including cancer development (1) and drug resistance (26). Recent studies show that activation of the ERK1/2 pathway is also involved in the transcriptional regulation of several important miRNAs.…”

Section: Discussionmentioning

confidence: 99%

MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non–small-cell lung cancer through BIM down-regulation

Romano

Acunzo

Garofalo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

150

137

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MicroRNAs (miRNAs) have an important role in the development of chemosensitivity or chemoresistance in different types of cancer. Activation of the ERK1/2 pathway is a major determinant of diverse cellular processes and cancer development and is responsible for the transcription of several important miRNAs. Here we show a link between the ERK1/2 pathway and BIM expression through miR-494. We blocked ERK1/2 nuclear activity through the overexpression of an ERK1/2 natural interactor, the protein PED/PEA15, and we performed a microRNA expression profile. miR-494 was the most down-regulated microRNA after ERK1/2 inactivation. Moreover, we found that miR-494 induced Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance in non–small-cell lung cancer (NSCLC) through the down-modulation of BIM. Elucidation of this undiscovered ERK1/2 pathway that regulates apoptosis and cell proliferation through miR-494 in NSCLC will greatly enhance our understanding of the mechanisms responsible for TRAIL resistance and will provide an additional arm for the development of anticancer therapies.

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Section: Discussionmentioning

confidence: 99%

MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non–small-cell lung cancer through BIM down-regulation

Romano

Acunzo

Garofalo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

150

137

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“…In particular, overexpression or activating mutation of the epidermal growth factor receptor (EGFR) gene (in tumors of the lung, breast, colon, ovary, and bladder) [5], activating mutation of RAS (in tumors of the pancreas, colon, and lung) [6], and activating mutation of RAF (in melanomas and tumors of the colon, ovary, and thyroid) [7] have been associated with cancer and found to result in the activation of MEK1/2 and ERK1/2 in most cases. Inhibition of the ERK pathway thus represents a promising strategy for cancer treatment [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Efficient induction of apoptotic cell death is essential for the development of effective cancer chemotherapy [9].…”

Section: Introductionmentioning

confidence: 99%

Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells

Tanimura

Uchiyama

Watanabe

et al. 2009

Biochemical and Biophysical Research Communications

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The extracellular signal-regulated kinase (ERK) signaling pathway is constitutively activated in many human tumor cell types. Given the cytoprotective role of this pathway, we examined whether its specific blockade might sensitize human tumor cells to the induction of apoptosis by various anticancer drugs. Although blockade of ERK signaling alone did not induce substantial cell death, it resulted in marked and selective enhancement of the induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the ERK pathway is constitutively activated. The synergistic activation of c-Jun NH 2 -terminal kinase by the combination of an ERK pathway inhibitor and a microtubule-destabilizing agent appeared to be responsible, at least in part, for this effect.These results suggest that administration of the combination of an ERK pathway inhibitor and a microtubule-destabilizing agent is a potential chemotherapeutic strategy for the treatment of tumor cells with constitutive activation of the ERK pathway.

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“…Noncatalytic activation of a few partners by c-Raf is well documented, but the biological outcomes of the ERK pathway are predominantly driven by the kinase activity, as evidenced, for example, by chemical inhibition (reviewed in Ref. 2). ERK is primarily located in the cytoplasm of resting cells, although overexpression results in cytoplasmic and nuclear localization (3).…”

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confidence: 99%

ERK Nuclear Translocation Is Dimerization-independent but Controlled by the Rate of Phosphorylation

Lidke

Huang

Post

et al. 2010

Journal of Biological Chemistry

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Upon activation, ERKs translocate from the cytoplasm to the nucleus. This process is required for the induction of many cellular responses, yet the molecular mechanisms that regulate ERK nuclear translocation are not fully understood. We have used a mouse embryo fibroblast ERK1-knock-out cell line expressing green fluorescent protein (GFP)-tagged ERK1 to probe the spatiotemporal regulation of ERK1. Real time fluorescence microscopy and fluorescence correlation spectroscopy revealed that ERK1 nuclear accumulation increased upon serum stimulation, but the mobility of the protein in the nucleus and cytoplasm remained unchanged. Dimerization of ERK has been proposed as a requirement for nuclear translocation. However, ERK1-⌬4, the mutant shown consistently to be dimerization-deficient in vitro, accumulated in the nucleus to the same level as wild type (WT), indicating that dimerization of ERK1 is not required for nuclear entry and retention. Consistent with this finding, energy migration Förster resonance energy transfer and fluorescence correlation spectroscopy measurements in living cells did not detect dimerization of GFP-ERK1-WT upon activation. In contrast, the kinetics of nuclear accumulation and phosphorylation of GFP-ERK1-⌬4 were slower than that of GFP-ERK1-WT. These results indicate that the differential shuttling behavior of the mutant is a consequence of delayed phosphorylation of ERK by MEK rather than dimerization. Our data demonstrate for the first time that a delay in cytoplasmic activation of ERK is directly translated into a delay in nuclear translocation.Stimulation of numerous cell surface receptors leads to activation of the Raf/MEK 7 /ERK signaling pathway. In this kinase cascade, Raf phosphorylates only MEK, and MEK phosphorylates only ERK, whereas ERK is able to phosphorylate many substrates in nearly all cell compartments (1). Noncatalytic activation of a few partners by c-Raf is well documented, but the biological outcomes of the ERK pathway are predominantly driven by the kinase activity, as evidenced, for example, by chemical inhibition (reviewed in Ref.2). ERK is primarily located in the cytoplasm of resting cells, although overexpression results in cytoplasmic and nuclear localization (3). It has long been recognized that in the course of physiological signal transduction, ERK accumulates in the nucleus after acute stimulation of the cell (3, 4). Nuclear translocation of ERK is required for cell cycle entry. Thus, retention of ERK in the cytoplasm alters neither ERK kinase activity nor phosphorylation of cytoplasmic substrates, whereas ERK-dependent transcription and cell proliferation are blocked (5). It has been demonstrated that ERK phosphorylates the Phe-Gly nucleoporins Nup50, Nup153, and Nup154, reducing importin-␤-mediated nucleocytoplasmic transport (6). This observation would expand the role of ERK nuclear entry to include the regulation of nucleocytoplasmic transport of certain classes of proteins while crossing the nucleopore.MEK functions as the cytoplasmic anchor for ERK su...

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Targeting the ERK signaling pathway in cancer therapy

Cited by 357 publications

References 58 publications

MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non–small-cell lung cancer through BIM down-regulation

MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non–small-cell lung cancer through BIM down-regulation

Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells

ERK Nuclear Translocation Is Dimerization-independent but Controlled by the Rate of Phosphorylation

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