Cell Survival through Trk Neurotrophin Receptors Is Differentially Regulated by Ubiquitination

Juan Carlos Arévalo, Janelle Waite, Rithwick Rajagopal, Mercedes Beyna, Zhe Yu Chen, Francis S. Lee, Moses V. Chao

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)549-559
Number of pages11
JournalNeuron
Volume50
Issue number4
DOIs
StatePublished - May 18 2006

Keywords

  • CELLBIO
  • MOLNEURO
  • SIGNALING

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