Editors' ChoiceReceptors

Notch-like Neurotrophin Receptor

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Science Signaling  23 Feb 2010:
Vol. 3, Issue 110, pp. ec63
DOI: 10.1126/scisignal.3110ec63

The p75 neurotrophin receptor binds to all members of the neurotrophin family and can interact with other receptors to promote signaling. On its own, p75 can also produce signals, which appear to require its proteolysis by a presenilin-dependent γ-secretase. In the case of the receptor Notch, such cleavage produces an intracellular domain (ICD) fragment that moves to the nucleus to regulate gene expression. Parkhurst et al. present evidence that the p75 ICD may similarly regulate gene expression. The authors created a fusion protein with p75 containing a transcriptional activator that would cause expression of green fluorescent protein (GFP) if that C-terminal fragment of the receptor reached the nucleus. Production of GFP was detected in human embryonic kidney (HEK) 293 cells transfected with the receptor construct, and this was prevented by inhibition of γ-secretase. In PC12 cells (a cell line with neuronal characteristics), the endogenous p75 protein or its ICD fragment was detected in the nucleus by immunofluorescence microscopy or cell fractionation. Chromatin immunoprecipitation experiments with an antibody to the ICD of p75 revealed association of the ICD with the promoter of the gene encoding cyclin E1 when PC12 cells were treated with nerve growth factor for 3 hours. Furthermore, overexpression of the p75 ICD in HeLa cells (a human cancer-derived cell line) decreased transcription of the gene encoding cyclin E1. The ICD can interact with multiple intracellular proteins and may thus influence numerous signaling events. Nevertheless, the experiments from Parkhust et al. indicate that a primary action of the p75 ICD (and possibly fragments of the related receptors) may be direct regulation of transcription in the nucleus.

C. N. Parkhurst, N. Zampieri, M. V. Chao, Nuclear localization of the p75 neurotrophin receptor intracellular domain. J. Biol. Chem. 285, 5361–5368 (2010). [Abstract] [Full Text]

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