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Updated: Aug 8, 2026

Comparative Strategies for Ubiquitination Detection in Mammalian Cell Lysates Using SMAD2/SMURF2 as a Model
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Comparative Strategies for Ubiquitination Detection in Mammalian Cell Lysates Using SMAD2/SMURF2 as a Model

Published on: April 17, 2026

Cell survival through Trk neurotrophin receptors is differentially regulated by ubiquitination

Juan Carlos Arévalo1, Janelle Waite, Rithwick Rajagopal

  • 1Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology, and Neuroscience, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA. arevalo@saturn.med.nyu.edu

Neuron
|May 17, 2006
PubMed

Insights

Neurotrophin signaling specificity is regulated by Trk receptor ubiquitination. The E3 ligase Nedd4-2 targets TrkA for degradation, influencing neuronal survival, but not TrkB receptors.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Neurotrophin signaling specificity relies on Trk receptor tyrosine kinases.
  • Activated Trk receptors undergo internalization and degradation, but underlying mechanisms are unclear.

Purpose of the Study:

  • To elucidate the mechanisms of Trk receptor downregulation after activation.
  • To identify factors involved in the ubiquitination and degradation of Trk receptors.

Main Methods:

  • Investigated Trk receptor ubiquitination in response to neurotrophins.
  • Identified and characterized the interaction between Nedd4-2 and TrkA.
  • Assessed the impact of Nedd4-2 expression on TrkA levels and neuronal survival.

Main Results:

  • Trk receptors are multimonoubiquitinated upon neurotrophin stimulation.
  • Nedd4-2 ubiquitin ligase binds to and ubiquitinates the TrkA receptor via a PPXY motif, leading to its downregulation.
  • Nedd4-2 expression affects NGF-dependent sensory neuron survival but not BDNF-dependent neurons.
  • Nedd4-2 does not bind or ubiquitinate TrkB receptors due to the absence of a PPXY motif.

Conclusions:

  • Nedd4-2-mediated ubiquitination is a key mechanism for regulating TrkA receptor levels and NGF-dependent neuronal survival.
  • Differential regulation of Trk receptors by ubiquitination fine-tunes neurotrophin signaling and neuronal fate.

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