Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL
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Background: Pim-1, 2 and 3 are a group of enzymes related to the calcium calmodulin family of protein kinases. Over-expression of Pim-1 and Pim-2 in mice promotes the development of lymphomas, and up-regulation of Pim expression has been observed in several human cancers. Results: Here we show that the pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. In vitro mapping showed that Pim-2 predominantly phosphorylated Ser112, while Pim-1 phosphorylated Ser112, but also Ser136 and Ser155 at a reduced rate compared to Ser112. Pim-3 was found to be the least specific for Ser112, and the most effective at phosphorylating Ser136 and Ser155. Pim-3 was also able to phosphorylate other sites in Bad in vitro, including Ser170, another potential in vivo site. Mutation of Ser136 to alanine prevented the phosphorylation of Ser112 and Ser155 by Pim kinases in HEK-293 cells, suggesting that this site must be phosphorylated first in order to make the other sites accessible. Pim phosphorylation of Bad was also found to promote the 14-3-3 binding of Bad and block its association with Bcl-X L. Conclusion: All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death.
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PIM kinases promote cancer cell survival by inhibiting apoptosis and by enhancing metabolism and motility via NOTCH1.
“PIM kinases promote cancer cell survival by inhibiting apoptosis for example through phosphorylation of substrates like BAD, and by enhancing metabolism and motility via NOTCH112–14”
From Endothelial Pim3 kinase protects the vascular barrier during lung metastasis (2024) · cites this paper as [12]
The Background and Discussion support a survival role for PIM kinases through phosphorylation of the pro-apoptotic protein BAD, and the Results report BAD binding to 14-3-3 and dissociation from Bcl-XL. Our copy does not support the additional claim that PIM kinases enhance metabolism or motility via NOTCH1. (LLM, conf=0.88)
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References 54 · Cited by 246
- Authors
- Macdonald, A., Campbell, D. G., Toth, R., McLauchlan, H., Hastie, C. J., & Arthur, J. S. C.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- Arthur, J Simon C
- Venue
- BMC Cell Biology
- Published
- 2006-01-10
- Volume
- 7
- Issue
- 1
- Pages
- 1-1
- ISSN
- 1471-2121 (ISSN-L)
- PMC
- PMC1368972
- OpenAlex
- W1490240498
- Cited by
- 246
- References
- 54
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 3 · 2023: 10 · 2022: 12 · 2021: 19 · 2020: 16 · 2019: 9 · 2018: 8 · 2017: 13 · 2016: 11 · 2015: 10 · 2014: 11 · 2013: 16 · 2012: 16
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- BMC Cell Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Pfizer
- GlaxoSmithKline
- University of Dundee
- Merck KGaA
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- PIM kinases, Bad, Bcl-xL, 14-3-3 binding, protein phosphorylation, Bcl-2 family proteins, apoptosis, cell proliferation, PIM-1, PIM2, PIM3
- MeSH terms
- Animals, Cells, Cultured, Humans, Peptide Mapping, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Serine, Protein Serine-Threonine Kinases, 14-3-3 Proteins, bcl-X Protein, bcl-Associated Death Protein, Mice, Proto-Oncogene Proteins c-pim-1
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