Tyrosine phosphatase SHP-2 is a mediator of activity-dependent neuronal excitotoxicity

Neurons 0301 basic medicine Brain-Derived Neurotrophic Factor Intracellular Signaling Peptides and Proteins Biological Transport Protein Tyrosine Phosphatase, Non-Receptor Type 11 Enzyme Activation Mice 03 medical and health sciences Animals Calcium Mitogen-Activated Protein Kinases Phosphorylation Protein Tyrosine Phosphatases Cells, Cultured
DOI: 10.1038/sj.emboj.7600522 Publication Date: 2005-01-13T18:01:39Z
ABSTRACT
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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