Ubiquitination of TrkA by Nedd4-2 regulates receptor lysosomal targeting and mediates receptor signaling.

摘要: The nerve growth factor receptor TrkA (tropomyosin-related kinase receptor) participates in the survival and differentiation of several neuronal populations. C-terminal tail contains a PPXY motif, binding site E3 ubiquitin-ligase Nedd4-2 (neural precursor cell expressed, developmentally down-regulated 4-2). In order to analyze role ubiquitination on function, we generated three mutants, by introducing point mutations conserved hydrophobic amino acids - Leu784 Val790 switched Ala. mutants co-localized co-immunoprecipitated more efficiently with consequently strong increase basal multimonoubiquitination mutant receptors was observed. addition, found decrease abundance because preferential sorting towards late endosome/lysosome pathway instead recycling back plasma membrane. Despite reduction amount membrane caused changes, were able activate signaling cascades even efficient promoting neurite outgrowth than wild-type receptor. Our results demonstrate that hydrophobicity regulates activity therefore controls turnover. does not interfere activation cascades, but rather potentiates leading differentiation.