title: SHP-1 negatively regulates neuronal survival by functioning as a TrkA phosphatase.
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.
authors.affiliation: Brain Tumor Research Centre, Montreal Neurological Institute, McGill University, Quebec, Canada.
authors.forename: H Nicholas
authors.initials: HN
authors.lastname: Marsh
authors.forename: Catherine I
authors.initials: CI
authors.lastname: Dubreuil
authors.forename: Celia
authors.initials: C
authors.lastname: Quevedo
authors.forename: Anna
authors.initials: A
authors.lastname: Lee
authors.forename: Marta
authors.initials: M
authors.lastname: Majdan
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Walsh
authors.forename: Sharon
authors.initials: S
authors.lastname: Hausdorff
authors.forename: Farid Arab
authors.initials: FA
authors.lastname: Said
authors.forename: Olga
authors.initials: O
authors.lastname: Zoueva
authors.forename: Maya
authors.initials: M
authors.lastname: Kozlowski
authors.forename: Katherine
authors.initials: K
authors.lastname: Siminovitch
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D016716:PC12 Cells; D051966:Phospholipase C gamma; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000166:cytology; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; C509250:Ptpn6 protein, rat; D010738:Type C Phospholipases; D051966:Phospholipase C gamma