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Cell survival through Trk neurotrophin receptors is differentially regulated by ubiquitination.

Specificity of neurotrophin factor signaling is dictated through the action of Trk receptor tyrosine kinases. Once activated, Trk receptors are internalized and targeted for degradation. However, the mechanisms implicated in this process are incompletely understood. Here we report that the Trk receptors are multimonoubiquitinated in response to neurotrophins. We have identified an E3 ubiquitin ligase, Nedd4-2, that associates with the TrkA receptor and is phosphorylated upon NGF binding. The binding of Nedd4-2 to TrkA through a PPXY motif leads to the ubiquitination and downregulation of TrkA. Activated TrkA receptor levels and the survival of NGF-dependent sensory neurons, but not BDNF-dependent sensory neurons, are directly influenced by Nedd4-2 expression. Unexpectedly, Nedd4-2 does not bind or ubiquitinate related TrkB receptors, due to the lack of a consensus PPXY motif. Our results indicate that Trk neurotrophin receptors are differentially regulated by ubiquitination to modulate the survival of neurons.

Pubmed ID: 16701206

Authors

  • ArĂ©valo JC
  • Waite J
  • Rajagopal R
  • Beyna M
  • Chen ZY
  • Lee FS
  • Chao MV

Journal

Neuron

Publication Data

May 18, 2006

Associated Grants

  • Agency: NICHD NIH HHS, Id: HD023315
  • Agency: NIMH NIH HHS, Id: MH068850
  • Agency: NINDS NIH HHS, Id: NS21072
  • Agency: NIGMS NIH HHS, Id: T32 GM007308

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Survival
  • Cells, Cultured
  • Endosomal Sorting Complexes Required for Transport
  • Fluorescent Antibody Technique
  • Humans
  • Molecular Sequence Data
  • Nerve Growth Factors
  • Neurons
  • RNA, Small Interfering
  • Rats
  • Receptor, trkA
  • Receptors, Nerve Growth Factor
  • Sequence Homology, Amino Acid
  • Transfection
  • Ubiquitin
  • Ubiquitin-Protein Ligases