Novel Membrane-Targeted ERK1 and ERK2 Chimeras Which Act as Dominant Negative, Isotype-Specific Mitogen-Activated Protein Kinase Inhibitors of Ras-Raf-Mediated Transcriptional Activation of c-<i>fos</i> in NIH 3T3 Cells

Hochholdinger, Franz; Baier, Gottfried; Nogalo, Anto; Bauer, Birgit; Grunicke, H.; Überall, Florian

doi:10.1128/mcb.19.12.8052

Cited by 34 publications

(37 citation statements)

References 102 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When dysregulated, this cascade plays a major role in various pathological conditions, particularly cancer (2). ERK1/2 is regulated in part by its subcellular localization (3). Recent work has shown that ERK localization within the cell may be controlled by phosphoprotein enriched in diabetes (PED, also known as PEA-15 [phosphoprotein enriched in astrocytes]), a small, death effector domaincontaining protein (4).…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

mentioning

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

View full text Add to dashboard Cite

show abstract

“…The p38/ERK2 constructs were gifts from Dr. Melanie Cobb (13). The HA-ERK1-CAAX-pEF and HA-ERK1-SAAX-pEF constructs were as described (15). Kinase-dead HA-ERK1(K71R)-CAAX-pEF was generated by using the QuikChange TM kit (Stratagene) using HA-ERK1-CAAX-pEF as template.…”

Section: Methodsmentioning

confidence: 99%

PEA-15 Binding to ERK1/2 MAPKs Is Required for Its Modulation of Integrin Activation

Chou

Hill

Hsieh

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Activation of Raf-1 suppresses integrin activation, potentially through the activation of extracellular signalregulated kinases 1 and 2 (ERK1/2). However, bulk ERK1/2 activation does not correlate with suppression. PEA-15 reverses suppression of integrin activation and binds ERK1/2. Here we report that PEA-15 reversal of integrin suppression depends on its capacity to bind ERK1/2, indicating that ERK1/2 function is indeed required for suppression. Mutations in either the death effector domain or C-terminal tail of PEA-15 that block ERK1/2 binding abrogated the reversal of integrin suppression. Furthermore, we used ERK/p38 chimeras and site-directed mutagenesis to identify ERK1/2 residues required for binding PEA-15. Mutations of residues that precede the ␣G helix and within the mitogenactivated protein kinase insert blocked ERK2 binding to PEA-15, but not activation of ERK2. These ERK2 mutants blocked the ability of PEA-15 to reverse suppression of integrin activation. Thus, PEA-15 regulation of integrin activation depends on its binding to ERK1/2. To directly test the role of ERK1/2 localization in suppression, we enforced membrane association of ERK1 and 2 by joining a membrane-targeting CAAX box sequence to them. Both ERK1-CAAX and ERK2-CAAX were membrane-localized and suppressed integrin activation. In contrast to suppression by membrane-targeted Raf-CAAX, suppression by ERK1/2-CAAX was not reversed by PEA-15. Thus, ERK1/2 are the Raf effectors for suppression of integrin activation, and PEA-15 reverses suppression by binding ERK1/2.

show abstract

“…Two recent molecular constructs can localize ERK signaling to permit a cell engineering approach to control localization. ERK chimeras that express the Ras farnesylation sequence at their C terminus (ERK1-CAAX and ERK2-CAAX) and are membranebound sequester endogenous ERK at the plasma membrane (1) and provide for plasma membrane-localized signaling. A catalytically inactive cytoplasmic MAP kinase phosphatase, MKP-3/Pyst1, which binds and sequesters ERK in the cytoplasm, but does not affect its activity (2,30), provides for cytosolic ERK signaling.…”

Section: Figmentioning

confidence: 99%

“…A change in cell motility is just one of the many pleiotropic effects of signaling mediated by the epidermal growth factor receptor (EGFR), 1 and it has been suggested that such specific cellular responses are determined by the spatial targeting of downstream signaling events. This simple concept is complicated by the fact that EGFR-mediated cell motility requires signaling through the ubiquitous intracellular effector, ERK (4), which is present in both the cytoplasmic and nuclear compartments.…”

mentioning

confidence: 99%

Membrane Proximal ERK Signaling Is Required for M-calpain Activation Downstream of Epidermal Growth Factor Receptor Signaling

Glading

Überall

Keyse

et al. 2001

Journal of Biological Chemistry

188

165

View full text Add to dashboard Cite

Localization of signaling is critical in directing cellular outcomes, especially in pleiotropic signaling pathways. The extracellular signal-regulated kinase (ERK)/ microtubule-associated protein kinase, which promotes cell migration, proliferation, and differentiation is found in the nucleus and throughout the cytoplasm. Recently, it has been shown that nuclear translocation of ERK is required for transcriptional changes and cell proliferation. However, the cellular consequences, of cytoplasmic signaling have not been defined. We explored whether cytoplasmic, specifically membrane-proximal, ERK signaling is involved in growth factor-induced cell motility. We previously have demonstrated that increased M-calpain activity downstream of epidermal growth factor receptor (EGFR)-mediated ERK activation is necessary for epidermal growth factor (EGF)-induced motility. Calpain isoforms also have been found in nuclear, cytosolic, and plasma membrane-associated compartments in a variety of cell types. We now employ cell engineering approaches to control localization of the upstream EGFR and ERK activities to examine the spatial effect of upstream signal locale on downstream calpain activity. With differential ligand-induced internalization and trafficking-restricted receptor variants, we find that calpain activity is triggered only by plasma membrane-restricted activated EGFR, not by internalized (although still active) EGFR. Cells transfected with membrane-targeted ERK1 and ERK2, which sequester endogenous ERKs, exhibited normal EGF-induced calpain activity. Transfection of an inactive ERK phosphatase (MKP-3/Pyst1) that sequesters ERK in the cytoplasm prevented calpain activation as well as deadhesion. These data strongly suggest that EGF-induced calpain activity can be enhanced near sites of membrane-proximal EGFR-mediated ERK signaling, providing insights about how calpain activity might be regulated and targeted to enhance its effects on adhesionrelated substrates.

show abstract

Novel Membrane-Targeted ERK1 and ERK2 Chimeras Which Act as Dominant Negative, Isotype-Specific Mitogen-Activated Protein Kinase Inhibitors of Ras-Raf-Mediated Transcriptional Activation of c-fos in NIH 3T3 Cells

Cited by 34 publications

References 102 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

PEA-15 Binding to ERK1/2 MAPKs Is Required for Its Modulation of Integrin Activation

Membrane Proximal ERK Signaling Is Required for M-calpain Activation Downstream of Epidermal Growth Factor Receptor Signaling

Contact Info

Product

Resources

About