A truncated fragment of Src protein kinase generated by calpain-mediated cleavage is a mediator of neuronal death in excitotoxicity

Hossain, M.Iqbal, Roulston, Carli L., Kamaruddin, M.Aizuddin, Chu, Percy W.Y., Ng, Dominic C.H., Dusting, Gregory J., Bjorge, Jeffrey D., Williamson, Nicholas A., Fujita, Donald J., Cheung, Steve N., Chan, Tung O., Hill, Andrew F. and Cheng, Heung-Chin 2013, A truncated fragment of Src protein kinase generated by calpain-mediated cleavage is a mediator of neuronal death in excitotoxicity, Journal of biological chemistry, vol. 288, no. 14, pp. 9696-9709.

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Title A truncated fragment of Src protein kinase generated by calpain-mediated cleavage is a mediator of neuronal death in excitotoxicity
Author(s) Hossain, M.Iqbal
Roulston, Carli L.
Kamaruddin, M.Aizuddin
Chu, Percy W.Y.
Ng, Dominic C.H.
Dusting, Gregory J.
Bjorge, Jeffrey D.
Williamson, Nicholas A.
Fujita, Donald J.
Cheung, Steve N.
Chan, Tung O.
Hill, Andrew F.
Cheng, Heung-Chin
Journal name Journal of biological chemistry
Volume number 288
Issue number 14
Start page 9696
End page 9709
Total pages 14
Publisher American Society for Biochemistry and Molecular Biology, Inc.
Place of publication Bethesda, Md.
Publication date 2013
ISSN 0021-9258
1083-351X
Keyword(s) akt
calpain
cell death
excitotoxicity
glutamate
neurons
src
stroke
Summary 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.
Language eng
Field of Research 111601 Cell Physiology
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Persistent URL http://hdl.handle.net/10536/DRO/DU:30055263

Document type: Journal Article
Collection: School of Life and Environmental Sciences
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