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Tyrosine phosphatase SHP‐2 is a mediator of activity‐dependent neuronal excitotoxicity
Author(s) -
Rusanescu Gabriel,
Yang Wentian,
Bai Ailin,
Neel Benjamin G,
Feig Larry A
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600522
Subject(s) - excitotoxicity , biology , tropomyosin receptor kinase b , microbiology and biotechnology , autophosphorylation , glutamate receptor , protein tyrosine phosphatase , neurotrophic factors , neurotrophin , calcium signaling , signal transduction , neuroscience , receptor , biochemistry , kinase , protein kinase a
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.