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| Subject Categories: Signal Transduction | Neuroscience |
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| The EMBO Journal
(2005) 24, 305–314, doi:10.1038/sj.emboj.7600522 Published online 13 January 2005 |
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| Tyrosine phosphatase SHP-2 is a mediator of activity-dependent neuronal excitotoxicity |
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| Gabriel Rusanescu1, Wentian Yang2, Ailin Bai2, Benjamin G Neel2 and Larry A Feig1 |
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1 Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA 2 Cancer Biology Program, Division of Hematology Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA To whom correspondence should be addressed Larry A Feig, Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA. Tel.: +1 617 636 6956; Fax: +1 617 636 2409; E-mail: larry.feig@tufts.edu Received 1 March 2004; Accepted 24 November 2004; Published online 13 January 2005. |
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| Abstract |
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| Calcium influx can promote neuronal differentiation and survival, at least in part by activating Ras and its downstream targets, including the Erk pathway. However, excessive calcium influx can initiate molecular signals leading to neuronal death during excitotoxicity or in neurodegenerative diseases. Here we describe a new signaling pathway associated with calcium influx that contributes to neuronal cell death in cerebellar neurons. Influx of calcium, mediated either by L-type voltage-sensitive calcium channels or glutamate receptors, is associated with the suppression of brain-derived neurotrophic factor (BDNF) activation of Ras and its effectors Erk and Akt. This is the result of enhanced association of the tyrosine phosphatase Shp-2 with TrkB receptors, which inhibits BDNF-induced TrkB autophosphorylation and activation. Deletion of the Shp2 gene in neuronal cultures reverses inhibition of TrkB function and increases neuronal survival after extended depolarization or glutamate treatment. These findings implicate Shp-2 in a feedback system initiated by calcium that negatively regulates neurotrophin signaling and sensitizes neurons to excitotoxicity. |
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| Keywords: BDNF, calcium, excitotoxicity, neurons, Shp-2 |
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