M Iqbal Hossain1, Ashfaqul Hoque1, Guillaume Lessene2, M Aizuddin Kamaruddin1, Percy W Y Chu1, Ivan H W Ng3, Sevgi Irtegun1, Dominic C H Ng1, Marie A Bogoyevitch1, Antony W Burgess2, Andrew F Hill1, Heung-Chin Cheng4. 1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, VIC, Australia. 2. Divisions of Chemical and Structural Biology, Walter and Eliza Institute for Medical Research, Parkville 3010, VIC, Australia. 3. 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. 4. 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.
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.
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: Gahana Advani; Ya Chee Lim; Bruno Catimel; Daisy Sio Seng Lio; Nadia L Y Ng; Anderly C Chüeh; Mai Tran; Mohd Ishtiaq Anasir; Heather Verkade; Hong-Jian Zhu; Benjamin E Turk; Thomas E Smithgall; Ching-Seng Ang; Michael Griffin; Heung-Chin Cheng Journal: Cell Commun Signal Date: 2017-08-07 Impact factor: 5.712
Authors: Irina Yu Petrushanko; Artem M Tverskoi; Evgeny P Barykin; Aleksandra V Petrovskaya; Maria A Strelkova; Olga G Leonova; Anastasia A Anashkina; Anna P Tolstova; Alexei A Adzhubei; Anna Yu Bogdanova; Alexander A Makarov; Vladimir A Mitkevich Journal: Cells Date: 2022-09-03 Impact factor: 7.666