The neogenin intracellular domain regulates gene transcription via nuclear translocation.
Neogenin is a multifunctional receptor implicated in axon navigation, neuronal differentiation, morphogenesis, and cell death. Very little is known about signaling downstream of neogenin. Because we found that the neogenin intracellular domain (NeICD) interacts with nuclear proteins implicated in transcription regulation, we investigated further whether neogenin signals similarly to the Notch receptor. We show here that neogenin is cleaved by gamma-secretase, an event that releases the complete NeICD. We also describe that NeICD is located at the nucleus, a feature regulated through a balance between nuclear import and export. NeICD triggers gene reporter transactivation and associates with nuclear chromatin. Direct transcriptional targets of NeICD were determined and were shown to be up-regulated in the presence of neogenin ligand. Together, we reveal here a novel aspect of neogenin signaling that relies on the direct implication of its intracellular domain in transcriptional regulation.
Goldschneider
David
D
Apoptosis, Cancer, and Development Laboratory, Equipe Labellisée La Ligue, CNRS UMR5238, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
Rama
Nicolas
N
Guix
Catherine
C
Mehlen
Patrick
P
D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D005786:Gene Expression Regulation; D015723:Gene Library; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
D018076:DNA, Complementary; D008565:Membrane Proteins; C091279:neogenin