Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling

Mol Cell. 2005 Oct 28;20(2):301-12. doi: 10.1016/j.molcel.2005.09.014.


Nerve growth factor (NGF) binding to p75(NTR) influences TrkA signaling, yet the molecular mechanism is unknown. We observe that NGF stimulates TrkA polyubiquitination, which was attenuated in p75(-/-) mouse brain. TrkA is a substrate of tumor necrosis factor receptor-associated factor 6 (TRAF6), and expression of K63R mutant ubiquitin or an absence of TRAF6 abrogated TrkA polyubiquitination and internalization. NGF stimulated formation of a TrkA/p75(NTR) complex through the p62 scaffold, recruiting the E3/TRAF6 and E2/UbcH7. Peptide targeted to the TRAF6 binding site present in p62 blocked interaction with TRAF6 and inhibited ubiquitination of TrkA, signaling, internalization, and NGF-dependent neurite outgrowth. Mutation of K485 to R blocked TRAF6 and NGF-dependent polyubiquitination of TrkA, resulting in retention of the receptor on the membrane and an absence in activation of specific signaling pathways. These findings reveal that polyubiquitination serves as a common platform for the control of receptor internalization and signaling.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Humans
  • Lysine / metabolism*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Nerve Growth Factors / metabolism*
  • Nerve Growth Factors / pharmacology
  • PC12 Cells
  • Polyubiquitin / metabolism*
  • Rats
  • Receptor, trkA / drug effects
  • Receptor, trkA / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Structure-Activity Relationship
  • TNF Receptor-Associated Factor 6 / metabolism


  • Nerve Growth Factors
  • TNF Receptor-Associated Factor 6
  • Polyubiquitin
  • Receptor, trkA
  • Lysine