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ItemAberrant regulation and function of Src family tyrosine kinases: Their potential contributions to glutamate-induced neurotoxicityHossain, MI ; Kamaruddin, MA ; Cheng, H-C (WILEY, 2012-08-01)Excitotoxicity, a major cause of neuronal death in acute and chronic neurodegenerative diseases and conditions such as stroke and Parkinson's disease, is initiated by overstimulation of glutamate receptors, leading to calcium overload in affected neurons. The sustained high concentration of intracellular calcium constitutively activates a host of enzymes, notably the calcium-activated proteases calpains, neuronal nitric oxide synthase (nNOS) and NADPH oxidase (NOX), to antagonise the cell survival signalling pathways and induce cell death. Upon overactivation by calcium, calpains catalyse limited proteolysis of specific cellular proteins to modulate their functions; nNOS produces excessive amounts of nitric oxide (NO), which, in turn, covalently modifies specific enzymes by S-nitrosylation; and NOX produces excessive amounts of reactive oxygen species (ROS) to inflict damage to key metabolic enzymes. Presumably, key regulatory enzymes governing cell survival and cell death are aberrantly modified and regulated by calpains, NO and ROS in affected neurons; these aberrantly modified enzymes then cooperate to induce the death of affected neurons. c-Src, an Src family kinase (SFK) member, is one of the aberrantly regulated enzymes involved in excitotoxic neuronal death. Herein we review how SFKs are functionally linked to the glutamate receptors and the biochemical and structural basis of the aberrant regulation of SFKs. Results in the literature suggest that SFKs are aberrantly activated by calpain-mediated truncation and S-nitrosylation. Thus, the aberrantly activated SFKs are targets for therapeutic intervention to reduce the extent of brain damage caused by stroke.
ItemA Truncated Fragment of Src Protein Kinase Generated by Calpain-mediated Cleavage Is a Mediator of Neuronal Death in ExcitotoxicityHossain, MI ; Roulston, CL ; Kamaruddin, MA ; Chu, PWY ; Ng, DCH ; Dusting, GJ ; Bjorge, JD ; Williamson, NA ; Fujita, DJ ; Cheung, SN ; Chan, TO ; Hill, AF ; Cheng, H-C (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2013-04-05)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.
ItemCSK-Homologous Kinasevan Roy, F ; Nimmrich, V ; Bespalov, A ; Möller, A ; Hara, H ; Turowec, JP ; St. Denis, NA ; Litchfield, DW ; Boucher, D ; Denault, J-B ; Matsuda, K ; Yuzaki, M ; Repeke, C ; Garlet, T ; Trombone, AP ; Garlet, G ; Repeke, C ; Garlet, T ; Silveira, EM ; Garlet, G ; Garlet, T ; Repeke, C ; Vieira, A ; Cunha, F ; Garlet, G ; Kubota, S ; Takigawa, M ; Soares, H ; Nolasco, S ; Gonçalves, J ; Bensussan, A ; Marie-Cardine, A ; Deswal, S ; Schamel, WWA ; Santos-Argumedo, L ; Deswal, S ; Schamel, WWA ; Bishop, GA ; Decker, DA ; Hostager, BS ; Bravo-Adame, ME ; Sandoval-Hernandez, MA ; Migueles-Lozano, OA ; Rosenstein, Y ; Johnson, P ; Samarakoon, A ; Saunders, AE ; Harder, KW ; Roberts, DD ; Soto-Pantoja, DR ; Isenberg, JS ; Lazo, PA ; Barcia, R ; Wu, H-J ; Muthusamy, N ; Bondada, S ; Levy, S ; Pawaria, S ; Binder, RJ ; Masai, H ; Hu, D ; Lahti, JM ; Singer, BB ; Horuk, R ; Miller, LJ ; Morisset, J ; Litchfield, DW ; Mistry, AR ; O’Callaghan, CA ; Fenton-May, AE ; O’Callaghan, CA ; Mistry, AR ; O’Callaghan, CA ; Reschen, M ; O’Callaghan, CA ; Willment, JA ; Brown, GD ; Rabinow, L ; Ness, SA ; Creutz, CE ; Yagishita-Kyo, N ; Inoue, M ; Nonaka, M ; Okuno, H ; Bito, H ; Okada, M ; Cheng, H-C ; Hossain, MI ; Kamaruddin, MA ; Chong, Y-P ; Sen, B ; Johnson, FM ; Pino, PA ; Cardona, AE ; Paroni, F ; Maedler, K ; Poon, RYC (Springer New York, 2012)