The p75 neurotrophin receptor (p75NTR) is a member of the tumour necrosis factor receptor superfamily and has many important functions, but the specific signalling pathways it uses to effect these functions remain unclear; this is in part due to a lack of reliable in vitro assays for analysing these pathways. Now (p. 447), Philip Barker and colleagues describe a novel cell-spreading bioassay in COS7 cells for analysing signalling cascades activated by p75NTR. Using this assay, the authors show that p75NTR acts through Rac1 to promote COS7 cell spreading, and this spreading requires the generation of the p75NTR intracellular domain (p75NTRICD) through the sequential ADAM17- and γ-secretase-dependent cleavage of p75NTR. The authors also demonstrate that p75NTR-dependent Rac1 activation requires the p75NTR adaptor protein NRAGE, and identify NEDD9 – a key regulator of cell shape and migration – as a novel NRAGE-binding protein that acts downstream of p75NTR in cell spreading. Together, these data suggest that p75NTR-dependent cell spreading is dependent on the generation of p75NTRICD, which then drives NRAGE- and NEDD9-dependent activation of Rac1. This is the first demonstration of a biochemical and functional link between these three molecules in a single cascade.

© 2015. Published by The Company of Biologists Ltd
2015