ERK1/2‐dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl‐1 and Bcl‐xL
Open accessAbstract
The proapoptotic protein Bim is expressed de novo following withdrawal of serum survival factors. Here, we show that Bim-/- fibroblasts and epithelial cells exhibit reduced cell death following serum withdrawal in comparison with their wild-type counterparts. In viable cells, Bax associates with Bcl-2, Bcl-x(L) and Mcl-1. Upon serum withdrawal, newly expressed Bim(EL) associates with Bcl-x(L) and Mcl-1, coinciding with the dissociation of Bax from these proteins. Survival factors can prevent association of Bim with pro-survival proteins by preventing Bim expression. However, we now show that even preformed Bim(EL)/Mcl-1 and Bim(EL)/Bcl-x(L) complexes can be rapidly dissociated following activation of ERK1/2 by survival factors. The dissociation of Bim from Mcl-1 is specific for Bim(EL) and requires ERK1/2-dependent phosphorylation of Bim(EL) at Ser(65). Finally, ERK1/2-dependent dissociation of Bim(EL) from Mcl-1 and Bcl-x(L) may play a role in regulating Bim(EL) degradation, since mutations in the Bim(EL) BH3 domain that disrupt binding to Mcl-1 cause increased turnover of Bim(EL). These results provide new insights into the role of Bim in cell death and its regulation by the ERK1/2 survival pathway.
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The RAS/MEK/ERK pathway regulates many of the same BCL-2 family genes via transcriptional and posttranslational mechanisms.
“This observation is consistent with reports that the RAS/MEK/ERK pathway also regulates many of these same genes via transcriptional and posttranslational mechanisms (27, 35–37).”
From Cotargeting a MYC/eIF4A-survival axis improves the efficacy of KRAS inhibitors in lung cancer (2023) · cites this paper as [36]
The Introduction (page not available) reports that Bim mRNA increases when ERK1/2 signaling is inactivated, and the Results section on ERK1/2 activation reports posttranslational phosphorylation and dissociation of BimEL from Mcl-1 and Bcl-xL. This supports regulation of Bim through both mechanisms, but this paper does not establish that the pathway regulates many BCL-2 family genes. (LLM, conf=0.85)
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- Authors
- Ewings, K. E., Hadfield‐Moorhouse, K., Wiggins, C. M., Wickenden, J. A., Balmanno, K., Gilley, R., Degenhardt, K., White, E., & Cook, S. J.
- Affiliations
- Babraham Institute (GB)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Cook, Simon J
- Venue
- The EMBO Journal
- Published
- 2007-05-24
- Volume
- 26
- Issue
- 12
- Pages
- 2856-2867
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1894764
- OpenAlex
- W2122549662
- Cited by
- 176
- References
- 45
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 5 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 11 · 2015: 8 · 2014: 11 · 2013: 10 · 2012: 22
- FWCI
- 6.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK
- Biotechnology and Biological Sciences Research Council (BBS/E/B/0000C199, BB/E02162X/1, BBS/E/B/0000H457, BBS/E/B/0000H151)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- BimEL, ERK1/2, Mcl-1, Bcl-xL, Bax, apoptosis, protein phosphorylation, BH3 domain, protein complex dissociation, cell survival factors, serum deprivation, pro-apoptotic proteins, Bcl-2 family proteins
- MeSH terms
- Bcl-2-Like Protein 11, Cell Line, Humans, Membrane Proteins, Neoplasm Proteins, Phosphorylation, Proto-Oncogene Proteins, Culture Media, Serum-Free, Proto-Oncogene Proteins c-bcl-2, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Apoptosis Regulatory Proteins, bcl-X Protein, Myeloid Cell Leukemia Sequence 1 Protein
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