ArticleThe Journal of biological chemistry2013
A truncated fragment of Src protein kinase generated by calpain-mediated cleavage is a mediator of neuronal death in excitotoxicity.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 46 citations in OpenAlex.
- Article
- The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2023Article
- N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection.Molecular & cellular proteomics : MCP · 2023Article
- CaMKIIα as a Promising Drug Target for Ischemic Grey Matter.Brain sciences · 2022Review
- Regulatory Roles of the N-Terminal Intrinsically Disordered Region of Modular Src.International journal of molecular sciences · 2022Review
- GABA Receptor Agonists Protect From Excitotoxic Damage Induced by AMPA in Oligodendrocytes.Frontiers in pharmacology · 2022Article
- MST1 mediates the N-methyl-D-aspartate-induced excitotoxicity in mouse cortical neurons.Cellular and molecular life sciences : CMLS · 2021Article
- A novel cell-penetrating peptide targeting calpain-cleavage of PSD-95 induced by excitotoxicity improves neurological outcome after stroke.Theranostics · 2021Article
- Differential Impact of Severity and Duration ofFrontiers in cellular neuroscience · 2021Article
- Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance.Breast cancer research : BCR · 2020Article
- Alveolar Stretch Activation of Endothelial Piezo1 Protects Adherens Junctions and Lung Vascular Barrier.American journal of respiratory cell and molecular biology · 2020Article
- Requirement of the acyl-CoA carrier ACBD6 in myristoylation of proteins: Activation by ligand binding and protein interaction.PloS one · 2020Article
- SULT4A1 Protects Against Oxidative-Stress Induced Mitochondrial Dysfunction in Neuronal Cells.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Quantitative proteomic analyses of dynamic signalling events in cortical neurons undergoing excitotoxic cell death.Cell death & disease · 2019Article
- Operational Experience of an Open-Access, Subscription-Based Mass Spectrometry and Proteomics Facility.Journal of the American Society for Mass Spectrometry · 2018Article
- Intramolecular Fuzzy Interactions Involving Intrinsically Disordered Domains.Frontiers in molecular biosciences · 2018Review
- Activation of Phosphotyrosine-Mediated Signaling Pathways in the Cortex and Spinal Cord of SOD1Neural plasticity · 2018Article
- Csk-homologous kinase (Chk) is an efficient inhibitor of Src-family kinases but a poor catalyst of phosphorylation of their C-terminal regulatory tyrosine.Cell communication and signaling : CCS · 2017Article
- miR-26a desensitizes non-small cell lung cancer cells to tyrosine kinase inhibitors by targeting PTPN13.Oncotarget · 2016Article
- Multiple pathways regulate Cten in colorectal cancer without a Tensin switch.International journal of experimental pathology · 2015Article
Corrections and comments
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Authors and funding
13 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Excitotoxicity resulting from overstimulation of glutamate receptors is a major cause of neuronal death in cerebral ischemic stroke. The overstimulated ionotropic glutamate receptors exert their neurotoxic effects in part by overactivation of calpains, which induce neuronal death by catalyzing limited proteolysis of specific cellular proteins. Here, we report that in cultured cortical neurons and in vivo in a rat model of focal ischemic stroke, the tyrosine kinase Src is cleaved by calpains at a site in the N-terminal unique domain. This generates a truncated Src fragment of ~52 kDa, which we localized predominantly to the cytosol. A cell membrane-permeable fusion peptide derived from the unique domain of Src prevents calpain from cleaving Src in neurons and protects against excitotoxic neuronal death. To explore the role of the truncated Src fragment in neuronal death, we expressed a recombinant truncated Src fragment in cultured neurons and examined how it affects neuronal survival. Expression of this fragment, which lacks the myristoylation motif and unique domain, was sufficient to induce neuronal death. Furthermore, inactivation of the prosurvival kinase Akt is a key step in its neurotoxic signaling pathway. Because Src maintains neuronal survival, our results implicate calpain cleavage as a molecular switch converting Src from a promoter of cell survival to a mediator of neuronal death in excitotoxicity. Besides unveiling a new pathological action of Src, our discovery of the neurotoxic action of the truncated Src fragment suggests new therapeutic strategies with the potential to minimize brain damage in ischemic stroke.
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