Src protein tyrosine kinase is critical for neuronal cell survival and demise — ASN Events
  1. Schedule
  2. Session Five - Poster Session A including Refreshments
  3. Src protein tyrosine kinase is critical for neuronal cell survival and demise

Src protein tyrosine kinase is critical for neuronal cell survival and demise (#104)

Md Ashfaqul Hoque 1 , M Iqbal Hossain 1 , Ching-Seng Ang 1 , Carli L Roulston 1 , Andrew F Hill 1 , Nicholas A Williamson 1 , Dominic CH Ng 1 , Heung-Chin Cheng 1
  1. University of Melbourne, Parkville, Vic, Australia
In mammalian central nervous system five members of Src family kinases (SFKs) are widely expressed, these are Src including others namely Fyn, Yes, Lyn and Lck. SFKs have been found to be involved in neuronal survival and neuronal cell death pathways; however the exact role of each of the members still remains unclear. Here we report the critical role of Src protein tyrosine kinase in supporting survival of cultured primary cortical neurons. Treatment with specific SFK inhibitor (A419259) significantly reduced cell viability that relates similar phenomenon when Src was specifically knocked-down using specific short-hairpin RNA (shRNA), demonstrating its indispensable role in survival of primary cortical neurons. Both Src kinase inhibitor treatment and Src knockdown caused inactivation of extracellular signal-regulated kinases 1 and 2 (Erk 1/2). Paradoxically, following excitotoxic stimulation by glutamate in cultured neurons, Src was cleaved by calpains in the unique domain to form a ~52kDa truncated Src fragment. Lentiviral expression of the recombinant truncated Src fragment lacking myristoylation and unique domain was sufficient to induce neuronal cell death. A cell membrane permeable fusion peptide derived the unique domain of Src prevented calpain from cleaving Src in neurons and also protected against excitotoxic neuronal death. Here the neurotoxic Src function was found to modulate Akt signalling pathways. Our findings demonstrate Src neurotrophic function in the physiological conditions as well as its conversion to a potent cell death executor in excitotoxicity.
  1. 1. Hossain, M.I., Roulston, C.L., Kamaruddin, M.A., Chu, P.W., Ng, D.C., Dusting, G.J., Bjorge, J.D., Williamson, N.A., Fujita, D.J., Cheung, S.N., Chan, T.O., Hill, A.F. and Cheng, H.C. 2013. A truncated fragment of Src protein kinase generated by calpain-mediated cleavage is a mediator of neuronal death in excitotoxicity. J Biol Chem, 288, 9696-709.