Research ArticleDEVELOPMENTAL NEUROSCIENCE

Temporal proteomics of NGF-TrkA signaling identifies an inhibitory role for the E3 ligase Cbl-b in neuroblastoma cell differentiation

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Science Signaling  28 Apr 2015:
Vol. 8, Issue 374, pp. ra40
DOI: 10.1126/scisignal.2005769

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Proteomic analysis reveals an inhibitor

Neurotrophins, such as nerve growth factor (NGF), control the differentiation and proliferation of neuronal precursors, and the outcome depends on the duration of the signal and neurotrophin-receptor pair. NGF binding to the receptor tyrosine kinase TrkA induces neuronal differentiation and neurite outgrowth. By mediating the attachment of ubiquitin chains, E3 ubiquitin ligases stimulate the internalization and degradation, and hence reduce the activity, of various receptors. Emdal et al. performed a temporal analysis by mass spectrometry of changes in the proteome in response to NGF in neuroblastoma cells and found that NGF not only promoted the activation of TrkA but also signaled its degradation by promoting the interaction of TrkA with the E3 ubiquitin ligase Cbl-b, which resulted in the ubiquitylation and degradation of both proteins. Neuroblastoma cells with reduced Cbl-b had increased TrkA signaling and produced longer neurites. In addition to identifying this inhibitory role for Cbl-b, the proteomic data are a resource for further investigation of TrkA signaling dynamics.

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