Journal
JOURNAL OF NEUROCHEMISTRY
Volume 117, Issue 3, Pages 479-493Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2011.07218.x
Keywords
degradation; differentiation; neurotrophin receptor; trafficking; ubiquitination; ubiquitin-ligase
Categories
Funding
- Instituto de Salud Carlos III - Ministerio de Sanidad y Consumo (FIS) [PI04/2537, PS09/00140]
- Ministry of Science and Innovation of Spain [SAF2005-02197, SAF2008-02271, SAF2007-60287]
- Government of Catalonia [SGR2005-00628]
- Ciberned [CB06/05/1104]
- 'Departament d'Universitat, Recerca i Societat de la Informacio' (DURSI)
- Government of Catalonia (DIUE)
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P>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 ubiquitin-ligase 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.
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