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

J Cell Biol. 2003 Dec 8;163(5):999-1010. doi: 10.1083/jcb.200309036.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Carrier Proteins / metabolism*
  • Cell Survival*
  • Cells, Cultured
  • Enzyme Activation
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred Strains
  • Mitogen-Activated Protein Kinases / metabolism
  • Nerve Growth Factor / metabolism
  • Neurons / cytology
  • Neurons / metabolism*
  • PC12 Cells
  • Phospholipase C gamma
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, trkA*
  • Signal Transduction
  • Sympathetic Nervous System / cytology
  • Type C Phospholipases / metabolism

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Nerve Growth Factor
  • Receptor, trkA
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn6 protein, mouse
  • Ptpn6 protein, rat
  • Type C Phospholipases
  • Phospholipase C gamma