|
Title:
|
Ubiquitination of TrkA by Nedd4-2 regulates receptor lysosomal targeting and mediates receptor signaling
|
|
Author:
|
Georgieva, Maya V.; Pablo Llavall, Yolanda de; Sanchis, Daniel; Comella i Carnicé, Joan Xavier; Llovera i Tomàs, Marta
|
|
Notes:
|
The nerve growth factor receptor TrkA (tropomyosin-related
kinase receptor) participates in the survival and differentiation
of several neuronal populations. The C-terminal tail of TrkA
contains a PPXY motif, the binding site of the E3 ubiquitinligase
Nedd4-2 (neural precursor cell expressed, developmentally
down-regulated 4-2). In order to analyze the role of
Nedd4-2 ubiquitination on TrkA function, we generated three
TrkA mutants, by introducing point mutations on conserved
hydrophobic amino acids – Leu784 and Val790 switched to
Ala. TrkA mutants co-localized and co-immunoprecipitated
more efficiently with Nedd4-2 and consequently a strong
increase in the basal multimonoubiquitination of the mutant
receptors was observed. In addition, we found a decrease in
TrkA abundance because of the preferential sorting of mutant
receptors towards the late endosome/lysosome pathway
instead of recycling back to the plasma membrane. Despite
the reduction in the amount of membrane receptor caused by
the C-terminal changes, TrkA mutants were able to activate
signaling cascades and were even more efficient in promoting
neurite outgrowth than the wild-type receptor. Our results
demonstrate that the C-terminal tail hydrophobicity of TrkA
regulates Nedd4-2 binding and activity and therefore controls
receptor turnover. In addition, TrkA multimonoubiquitination
does not interfere with the activation of signaling cascades,
but rather potentiates receptor signaling leading to differentiation.
The work was supported by the Instituto de Salud Carlos III – Ministerio de Sanidad y Consumo (FIS) (PI04/2537 and PS09/ 00140) to ML, the Ministry of Science and Innovation of Spain (SAF2005-02197 and SAF2008-02271) to DS and SAF2007-60287, Programa de Suport a Grups de Recerca from the Government of Catalonia (SGR2005-00628) and Ciberned (CB06/05/1104) to JXC. MVG is supported by ‘Departament d’Universitat, Recerca i Societat de la Informacio’ (DURSI) and the European Social Fund from the Government of Catalonia (DIUE). |
|
Subject(s):
|
-Degradation
-Differentiation
-Neurotrophin receptor |
|
Rights:
|
(c) Wiley, 2011
info:eu-repo/semantics/restrictedAccess |
|
Document type:
|
article
publishedVersion |
|
Published by:
|
Wiley
|
|
Share:
|
|
