Pancortin-2 Interacts with WAVE1 and Bcl-xL in a Mitochondria-Associated Protein Complex That Mediates Ischemic Neuronal Death
Open accessAbstract
The actin-modulating protein Wiskott-Aldrich syndrome protein verprolin homologous-1 (WAVE1) and a novel CNS-specific protein, pancortin, are highly enriched in adult cerebral cortex, but their functions are unknown. Here we show that WAVE1 and pancortin-2 interact in a novel cell death cascade in adult, but not embryonic, cerebral cortical neurons. Focal ischemic stroke induces the formation of a protein complex that includes pancortin-2, WAVE1, and the anti-apoptotic protein Bcl-xL. The three-protein complex is associated with mitochondria resulting in increased association of Bax with mitochondria, cytochrome c release, and neuronal apoptosis. In pancortin null mice generated using a Cre-loxP system, ischemia-induced WAVE1–Bcl-xL interaction is diminished, and cortical neurons in these mice are protected against ischemic injury. Thus, pancortin-2 is a mediator of ischemia-induced apoptosis of neurons in the adult cerebral cortex and functions in a novel mitochondrial/actin-associated protein complex that sequesters Bcl-xL.
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This protein complex is associated with mitochondria and recruits Bax, which is involved in ischemic stroke-induced apoptosis.
“This protein complex is associated with mitochondria and recruits Bax, which is involved in ischemic stroke-induced apoptosis83.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [83]
The Results section reports that the WAVE1/pancortin-2/Bcl-xL complex is associated with mitochondria and that Bax translocation to mitochondria is reduced after ischemia in mice lacking pancortin-2. The Discussion proposes that the complex may facilitate Bax translocation and neuronal apoptosis, but does not establish that the complex directly recruits Bax as the claim states. Page numbers were not available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn the brain, focal ischemic stroke induces the formation of a protein complex of WAVE1, pancortin-2 and the antiapoptotic protein Bcl-xL.
“In the brain, focal ischemic stroke induces the formation of a protein complex of WAVE1, pancortin-2 and the antiapoptotic protein Bcl-xL.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [83]
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Cites
Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies
Kim, H., Rafiuddin-Shah, M., Tu, H.-C., Jeffers, J. R., Zambetti, G. P., Hsieh, J. J.-D., & Cheng, E. H.-Y. (2006) · Nature Cell Biology · doi:10.1038/ncb1499 · Cited by 874 · see citing works
Takenawa, T., & Miki, H. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.10.1801 · Cited by 604 · see citing works
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Mitochondria in neuroplasticity and neurological disorders
Mattson, M. P., Gleichmann, M., & Cheng, A. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.010 · Cited by 1,081 · see citing works
Self-citationThe WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
- Authors
- Cheng, A., Arumugam, T. V., Liu, D., Khatri, R. G., Mustafa, K., Kwak, S., Ling, H.-P., Gonzales, C., Xin, O., Jo, D.-G., Guo, Z., Mark, R. J., & Mattson, M. P.
- Affiliations
- National Institute on Aging (US)
- National Institutes of Health (US)
- Wyeth (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Johns Hopkins University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-02-14
- Volume
- 27
- Issue
- 7
- Pages
- 1519-1528
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6673736
- OpenAlex
- W2018026238
- Cited by
- 56
- References
- 2
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 3
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- WAVE1, Bcl-xL, ischemic neuronal death, focal cerebral ischemia, mitochondrial protein complexes, actin cytoskeleton, Bax, cytochrome c release, neuronal apoptosis, cerebral cortex, ischemic stroke
- MeSH terms
- Animals, Cells, Cultured, Cerebral Cortex, Brain Ischemia, Embryo, Mammalian, Glycoproteins, Immunohistochemistry, Functional Laterality, Male, Mitochondria, Neurons, Time Factors, Blotting, Western, Extracellular Matrix Proteins, Cell Death, Rats, Wistar, Mice, Knockout, Cytochromes c, Immunoprecipitation, Green Fluorescent Proteins, bcl-X Protein, Wiskott-Aldrich Syndrome Protein Family, Mice, Rats
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