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.
Highlights
The survival of cells of the nervous system is dependent on the action of neurotrophic factors that prevent both intrinsic and extrinsic cues from inducing cellular apoptosis
We examined the role of the SHP-1 pTyr phosphatase in neurotrophin-mediated cell survival and signal transduction
Our results indicate that SHP-1 is a TrkA phosphatase in PC12 cells and in sympathetic neurons in culture and in vivo, and that it functions to ensure low levels of basal TrkA activation and to attenuate long-term TrkA signaling in the presence of NGF
Summary
The survival of cells of the nervous system is dependent on the action of neurotrophic factors that prevent both intrinsic and extrinsic cues from inducing cellular apoptosis. Neurotrophic target-derived factors, such as NGF, retrogradely determine neuronal survival by suppressing autocrine and p75NTR-induced apoptotic signals. This interplay between life and death signals precisely regulates neuron number during development. TrkA functions by phosphorylating on tyrosine and thereby activating signaling proteins involved in neuronal survival and differentiation, paradoxically, it activates the phosphotyrosine (pTyr) phosphatase SHP-1 (Vambutas et al, 1995) Because phosphatases such as SHP-1 can have both positive and negative effects on receptor tyrosine kinase signaling (Tonks and Neel, 2001), we asked about the function and mechanism of action of this protein in NGF signal transduction
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