Article
- The EMBO Journal (2005) 24, 305 - 314
- doi:10.1038/sj.emboj.7600522
Published online: 13 January 2005
Subject Categories:
Tyrosine phosphatase SHP-2 is a mediator of activity-dependent neuronal excitotoxicity
Gabriel Rusanescu1, Wentian Yang2, Ailin Bai2, Benjamin G Neel2 and Larry A Feig1
- Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA
- Cancer Biology Program, Division of Hematology Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Correspondence to:
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
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.
Keywords:
- BDNF,
- calcium,
- excitotoxicity,
- neurons,
- Shp-2
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Protein palmitoylation: a regulator of neuronal development and function
Nature Reviews Neuroscience Review (01 Oct 2002)
NEWS AND VIEWS
Neurobiology Exciting neurotrophins
Nature News and Views (28 Oct 1999)
Neurobiology Neurotrophin channels excitement
Nature News and Views (17 Oct 2002)
RESEARCH
TRPC channels promote cerebellar granule neuron survival
Nature Neuroscience Article (01 May 2007)
BDNF-mediated neurotransmission relies upon a myosin VI motor complex
Nature Neuroscience Article (01 Aug 2006)
