Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology
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Carrier Proteins / metabolism*
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Cell Survival*
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Cells, Cultured
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Enzyme Activation
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred Strains
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Mitogen-Activated Protein Kinases / metabolism
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Nerve Growth Factor / metabolism
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Neurons / cytology
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Neurons / metabolism*
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PC12 Cells
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Phospholipase C gamma
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / metabolism*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Rats
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Rats, Sprague-Dawley
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Receptor, trkA*
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Signal Transduction
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Sympathetic Nervous System / cytology
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Type C Phospholipases / metabolism
Substances
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Carrier Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Proto-Oncogene Proteins
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Nerve Growth Factor
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Receptor, trkA
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn6 protein, mouse
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Ptpn6 protein, rat
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Type C Phospholipases
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Phospholipase C gamma