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Published 8 December 2003. doi:10.1083/jcb.200309036
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© The Rockefeller University Press, 0021-9525/2003/12/999 $8.00
The Journal of Cell Biology, Volume 163, Number 5, 999-1010

Article

 SHP-1 negatively regulates neuronal survival by functioning as a TrkA phosphatase

H. Nicholas Marsh1, Catherine I. Dubreuil1, Celia Quevedo2, Anna Lee3, Marta Majdan1, Gregory S. Walsh1,3, Sharon Hausdorff4, Farid Arab Said5, Olga Zoueva6, Maya Kozlowski6, Katherine Siminovitch7, Benjamin G. Neel4, Freda D. Miller1,3,8 and David R. Kaplan1,2,8

1 Brain Tumor Research Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada
2 Cancer Research Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
3 Developmental Biology Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
4 Cancer Biology Program, Division of Medicine, Harvard Medical School, Beth Israel Hospital, Boston, MA 02215
5 Aegera Therapeutics, Inc., Montreal, Quebec H3E 1A8, Canada
6 Health Canada, Biologics and Genetics Therapies Directorate, Center for Biologics Research, Ottawa, Ontario K1A 0L2, Canada
7 Department of Medicine, University of Toronto, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
8 Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Address correspondence to D. Kaplan, Cancer Research Program, Hospital for Sick Children, 555 University Ave., Toronto, Ontario, M5G 1X8. Tel.: (416) 813-7654, ext. 1433. Fax: (416) 813-2212. email: dkaplan{at}sickkids.ca

Nerve growth factor (NGF) mediates the survival and differentiation of neurons by stimulating the tyrosine kinase activity of the TrkA/NGF receptor. Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. Expression of SHP-1 in sympathetic neurons induced apoptosis and TrkA dephosphorylation. Conversely, inhibition of endogenous SHP-1 with a dominant-inhibitory mutant stimulated basal tyrosine phosphorylation of TrkA, thereby promoting NGF-independent survival and causing sustained and elevated TrkA activation in the presence of NGF. Mice lacking SHP-1 had increased numbers of sympathetic neurons during the period of naturally occurring neuronal cell death, and when cultured, these neurons survived better than wild-type neurons in the absence of NGF. These data indicate that SHP-1 can function as a TrkA phosphatase, controlling both the basal and NGF-regulated level of TrkA activity in neurons, and suggest that SHP-1 regulates neuron number during the developmental cell death period by directly regulating TrkA activity.

Key Words: neurotrophins; NGF; sympathetic neurons; PC12 cells; apoptosis

C.I. Dubreuil and C. Quevedo contributed equally to this work.

H.N. Marsh's present address is Archemix Corporation, 1 Hampshire St., Cambridge, MA 02139.

Abbreviations used in this paper: Ad, adenovirus; MOI, multiplicity of infection; P, postnatal day; SCG, superior cervical ganglia; wt, wild-type.


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