dc.contributor.author |
Georgieva, Maya V. |
dc.contributor.author |
Pablo Llavall, Yolanda de |
dc.contributor.author |
Sanchis, Daniel |
dc.contributor.author |
Comella i Carnicé, Joan Xavier |
dc.contributor.author |
Llovera i Tomàs, Marta |
dc.date |
2016-06-01T08:30:17Z |
dc.date |
2011 |
dc.date |
10000-01-01 |
dc.identifier |
0022-3042 |
dc.identifier |
http://hdl.handle.net/10459.1/57138 |
dc.identifier |
https://doi.org/10.1111/j.1471-4159.2011.07218.x |
dc.identifier.uri |
http://hdl.handle.net/10459.1/57138 |
dc.description |
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. |
dc.description |
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). |
dc.language |
eng |
dc.publisher |
Wiley |
dc.relation |
MIECI/PN2004-2007/SAF2005-02197 |
dc.relation |
MICINN/PN2008-2011/SAF2008-02271 |
dc.relation |
MIECI/PN2004-2007/SAF2007-60287 |
dc.relation |
Reproducció del document publicat a https://doi.org/10.1111/j.1471-4159.2011.07218.x |
dc.relation |
Journal of Neurochemistry, 2011, vol. 117, núm. 3 |
dc.rights |
(c) Wiley, 2011 |
dc.rights |
info:eu-repo/semantics/restrictedAccess |
dc.subject |
Degradation |
dc.subject |
Differentiation |
dc.subject |
Neurotrophin receptor |
dc.title |
Ubiquitination of TrkA by Nedd4-2 regulates receptor lysosomal targeting and mediates receptor signaling |
dc.type |
article |
dc.type |
publishedVersion |