ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL

Ewings, Katherine; Hadfield-Moorhouse, Kathryn; Wiggins, Ceri M.; Wickenden, Julie A; Balmanno, Kathryn; Gilley, Rebecca; Degenhardt, Kurt; White, Eileen; Cook, Simon J.

doi:10.1038/sj.emboj.7601723

Cited by 157 publications

(187 citation statements)

References 47 publications

(113 reference statements)

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“…32,34,35 This study provides evidence that LX might affect these pathways. Incubation of macrophages with staurosporine induces a rapid activation of JNK and p38 MAPKs, but not of ERK, a classic survival pathway.…”

Section: Discussionmentioning

confidence: 86%

Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways

et al. 2010

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Lipoxin A 4 (LXA 4 ) is an endogenous lipid mediator that requires transcellular metabolic traffic for its synthesis. The targets of LXA 4 on neutrophils are well described, contributing to attenuation of inflammation. However, effects of lipoxins on macrophage are less known, particularly the action of LXA 4 on the regulation of apoptosis of these cells. Our data show that pretreatment of human or murine macrophages with LXA 4 at the concentrations prevailing in the course of resolution of inflammation (nanomolar range) significantly inhibits the apoptosis induced by staurosporine, etoposide and S-nitrosoglutathione or by more pathophysiological stimuli, such as LPS/IFNc challenge. The release of mitochondrial mediators of apoptosis and the activation of caspases was abrogated in the presence of LXA 4 . In addition to this, the synthesis of reactive oxygen species induced by staurosporine was attenuated and antiapoptotic proteins of the Bcl-2 family accumulated in the presence of lipoxin. Analysis of the targets of LXA 4 identified an early activation of the PI3K/Akt and ERK/Nrf-2 pathways, which was required for the observation of the antiapoptotic effects of LXA 4 . These data suggest that the LXA 4 , released after the recruitment of neutrophils to sites of inflammation, exerts a protective effect on macrophage viability that might contribute to a better resolution of inflammation.

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Section: Discussionmentioning

confidence: 86%

Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways

et al. 2010

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“…Two other BH3-only proteins, BIM and PUMA, stabilize MCL-1 via a mechanism that requires their BH3 domains, 21,37 and interaction of BIM EL with BCL-2 also reduces its turnover. 38 Although further studies are required to reconcile these differing results, together they highlight the critical role that interactions between BH3-only proteins and their pro-survival partners have in regulating the stability of multiple BCL-2 family proteins.…”

Section: Discussionmentioning

confidence: 99%

NOXA, a sensor of proteasome integrity, is degraded by 26S proteasomes by an ubiquitin-independent pathway that is blocked by MCL-1

et al. 2012

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Ubiquitin (Ub)-mediated proteasome-dependent proteolysis is critical in regulating multiple biological processes including apoptosis. We show that the unstructured BH3-only protein, NOXA, is degraded by an Ub-independent mechanism requiring 19S regulatory particle (RP) subunits of the 26S proteasome, highlighting the possibility that other unstructured proteins reported to be degraded by 20S proteasomes in vitro may be bona fide 26S proteasome substrates in vivo. A lysine-less NOXA (NOXA-LL) mutant, which is not ubiquitinated, is degraded at a similar rate to wild-type NOXA. Myeloid cell leukemia 1, but not other antiapoptotic BCL-2 family proteins, stabilizes NOXA by interaction with the NOXA BH3 domain. Depletion of 19S RP subunits, but not alternate proteasome activator REG subunits, increases NOXA half-life in vivo. A NOXA-LL mutant, which is not ubiquitinated, also requires an intact 26S proteasome for degradation. Depletion of the 19S non-ATPase subunit, PSMD1 induces NOXA-dependent apoptosis. Thus, disruption of 26S proteasome function by various mechanisms triggers the rapid accumulation of NOXA and subsequent cell death strongly implicating NOXA as a sensor of 26S proteasome integrity.

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“…24,29,30 More recently, it has been demonstrated that ERK1/2 activation can inhibit the binding of BIM EL to BCL-2 family proteins such as BCL-x L and MCL-1. 25,31 In serum-starved cells newly synthesized BIM EL associates with BCL-x L and MCL-1 but re-stimulation of cells with growth factors promotes the rapid dissociation of BIM EL :BCL-x L or BIM EL :MCL-1 complexes and activation of ERK1/2 is necessary and sufficient for this 25 (Figure 1). As BIM EL needs to engage with pro-survival proteins to kill cells this represents an additional survival mechanism.…”

Section: Erk1/2-dependent Regulation Of Bh3-only Proteinsmentioning

confidence: 99%

“…In addition to regulation of transcription, BIM EL is phosphorylated at multiple sites in response to selective activation of the ERK1/2 pathway 17 and this has the effect of promoting the ubiquitination and proteasome-dependent turnover of BIM EL 23 ( Figure 1). BIM EL is phosphorylated directly by ERK1/2 at up to four different sites; [24][25][26] the exon unique to BIM EL encodes three ERK1/2 phosphorylation sites and a DEF-type ERK1/2 docking domain. 27,28 Of these three Ser 69 (Ser 65 in mouse and rat) appears to be a key signal for BIM EL turnover as S 69 A or S 69 G mutants are defective in turnover, accumulate to higher levels than wild-type protein, and may exhibit enhanced toxicity.…”

Section: Erk1/2-dependent Regulation Of Bh3-only Proteinsmentioning

confidence: 99%

Tumour cell survival signalling by the ERK1/2 pathway

2008

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Several advances in recent years have focused increasing attention on the role of the RAF-MEK-ERK1/2 pathway in promoting cell survival. The demonstration that BRAF is a human oncogene mutated at high frequency in melanoma, thyroid and colon cancer has provided a pathophysiological context, whilst the description of potent and highly selective inhibitors of BRAF or MEK has allowed a more informed and rational intervention in both normal and tumour cells. In addition, separate studies have uncovered new mechanisms by which the ERK1/2 pathway can control the activity or abundance of members of the BCL-2 protein family to promote cell survival. It is now apparent that various oncogenes co-opt ERK1/2 signalling to de-regulate these BCL-2 proteins and this contributes to, and even underpins, survival signalling in some tumours. New oncogene-targeted therapies allow direct or indirect inhibition of ERK1/2 signalling and can cause quite striking tumour cell death. In other cases, inhibition of the ERK1/2 pathway may be more effective in combination with other conventional and novel therapeutics. Here, we review recent advances in our understanding of how the ERK1/2 pathway regulates BCL-2 proteins to promote survival, how this is de-regulated in tumour cells and the opportunities this might afford with the use of new targeted therapies.

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ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL

Abstract: The proapoptotic protein Bim is expressed de novo following withdrawal of serum survival factors. Here, we show that BimÀ/À fibroblasts and epithelial cells exhibit reduced cell death following serum withdrawal in comparison with their wild-type counterparts.

Cited by 157 publications

References 47 publications

Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways

Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways

NOXA, a sensor of proteasome integrity, is degraded by 26S proteasomes by an ubiquitin-independent pathway that is blocked by MCL-1

Tumour cell survival signalling by the ERK1/2 pathway

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