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.
Arévalo
Juan Carlos
JC
Molecular 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
Waite
Janelle
J
Rajagopal
Rithwick
R
Beyna
Mercedes
M
Chen
Zhe-Yu
ZY
Lee
Francis S
FS
Chao
Moses V
MV
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport; D005455:Fluorescent Antibody Technique; D006801:Humans; D008969:Molecular Sequence Data; D000075702:Nedd4 Ubiquitin Protein Ligases; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D056827:Endosomal Sorting Complexes Required for Transport; D009414:Nerve Growth Factors; D034741:RNA, Small Interfering; D017475:Receptors, Nerve Growth Factor; D025801:Ubiquitin; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618484:Nedd4 protein, rat; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases; D020917:Receptor, trkA