title: Dual role of Src kinase in governing neuronal survival.
abstract: BACKGROUND
  Src-family kinases (SFKs) are involved in neuronal survival and their aberrant regulation contributes to neuronal death. However, how they control neuronal survival and death remains unclear.
  
  
  OBJECTIVE
  To define the effect of inhibition of Src activity and expression on neuronal survival.
  
  
  RESULTS
  In agreement with our previous findings, we demonstrated that Src was cleaved by calpain to form a 52-kDa truncated fragment in neurons undergoing excitotoxic cell death, and expression of the recombinant truncated Src fragment induced neuronal death. The data confirm that the neurotoxic signaling pathways are intact in the neurons we used for our study. To define the functional role of neuronal SFKs, we treated these neurons with SFK inhibitors and discovered that the treatment induced cell death, suggesting that the catalytic activity of one or more of the neuronal SFKs is critical to neuronal survival. Using small hairpin RNAs that suppress Src expression, we demonstrated that Src is indispensable to neuronal survival. Additionally, we found that neuronal death induced by expression of the neurotoxic truncated Src mutant, treatment of SFK inhibitors or knock-down of Src expression caused inhibition of the neuroprotective protein kinases Erk1/2, or Akt.
  
  
  CONCLUSIONS
  Src is critical to both neuronal survival and death. Intact Src sustains neuronal survival. However, in the excitotoxic condition, calpain cleavage of Src generates a neurotoxic truncated Src fragment. Both intact Src and the neurotoxic truncated Src fragment exert their biological actions by controlling the activities of neuroprotective protein kinases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, VIC, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Iqbal Hossain
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, VIC, Australia.
authors.forename: Ashfaqul
authors.initials: A
authors.lastname: Hoque
authors.affiliation: Divisions of Chemical and Structural Biology, Walter and Eliza Institute for Medical Research, Parkville 3010, VIC, Australia.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lessene
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, VIC, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Aizuddin Kamaruddin
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, VIC, Australia.
authors.forename: Percy W Y
authors.initials: PW
authors.lastname: Chu
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, VIC, Australia; Department of Biochemistry and Molecular Biology, Monash University, Melbourne 3800, VIC, Australia.
authors.forename: Ivan H W
authors.initials: IH
authors.lastname: Ng
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, VIC, Australia.
authors.forename: Sevgi
authors.initials: S
authors.lastname: Irtegun
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, VIC, Australia.
authors.forename: Dominic C H
authors.initials: DC
authors.lastname: Ng
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, VIC, Australia.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Bogoyevitch
authors.affiliation: Divisions of Chemical and Structural Biology, Walter and Eliza Institute for Medical Research, Parkville 3010, VIC, Australia.
authors.forename: Antony W
authors.initials: AW
authors.lastname: Burgess
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, VIC, Australia.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Hill
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, VIC, Australia. Electronic address: heung@unimelb.edu.au.
authors.forename: Heung-Chin
authors.initials: HC
authors.lastname: Cheng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002154:Calpain / Q000378:metabolism; D002470:Cell Survival; D005455:Fluorescent Antibody Technique; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000201:enzymology*; D010446:Peptide Fragments / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D019061:src-Family Kinases; D002154:Calpain
keywords: Akt; Calpain; Excitotoxicity; NMDA receptor; Src kinase