Neurotrophin or proneurotrophin signalling promotes p75NTR cleavage by gamma-secretase, allowing the release of p75 ICD and NRIF. This mechanism was shown in sympathetic neurons.
Gamma-secretase can be activated in a number of ways, including signalling via p75NTR. The phorbol esther PMA induces p75 cleavage, followed by NRIF nuclear translocation, after 30 min. Neurotrophin binding to p75, instead, triggers the same events only after 12 h.