In vivo regulation of NGF-mediated functions by Nedd4-2 ubiquitination of TrkA.
Trk neurotrophin receptor ubiquitination in response to ligand activation regulates signaling, trafficking, and degradation of the receptors. However, the in vivo consequences of Trk ubiquitination remain to be addressed. We have developed a mouse model with a mutation in the TrkA neurotrophin receptor (P782S) that results in reduced ubiquitination due to a lack of binding to the E3 ubiquitin ligase, Nedd4-2. In vivo analyses of TrkAP782S indicate that defective ubiquitination of the TrkA mutant results in an altered trafficking and degradation of the receptor that affects the survival of sensory neurons. The dorsal root ganglia from the TrkAP782S knock-in mice display an increased number of neurons expressing CGRP and substance P. Moreover, the mutant mice show enhanced sensitivity to thermal and inflammatory pain. Our results indicate that the ubiquitination of the TrkA neurotrophin receptor plays a critical role in NGF-mediated functions, such as neuronal survival and sensitivity to pain.
Departments of Cell Biology and Pathology, Biochemistry and Molecular Biology, Instituto de Neurociencias de Castilla y León (INCyL), Universidad de Salamanca, Salamanca 37007, Spain, Neural Development Group, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, and Institute of Biomedical Research of Salamanca, Salamanca 37007, Spain.
Tao
T
Yu
Laura
L
Calvo
Begoña
B
Anta
Saray
S
López-Benito
Roger
R
López-Bellido
Cristina
C
Vicente-García
Lino
L
Tessarollo
Raquel E
RE
Rodriguez
Juan C
JC
Arévalo
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism; D006358:Hot Temperature; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D000075702:Nedd4 Ubiquitin Protein Ligases; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D056827:Endosomal Sorting Complexes Required for Transport; D013373:Substance P; D020932:Nerve Growth Factor; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D020917:Receptor, trkA; D015740:Calcitonin Gene-Related Peptide
TrkA neurotrophin receptor; neurotrophins; pain; ubiquitination