Individual and combined effects of TrkA and p75NTR nerve growth factor receptors -: A role for the high affinity receptor site

A long-standing question in neurotrophin signal transduction is whether heteromeric TrkA-p75(NTR) complexes possess signaling capabilities that are significantly different from homo-oligomeric TrkA or p75(NTR) alone. To address this issue, various combinations of transfected PC12 cells expressing a platelet-derived growth factor receptor-TrkA chimera and the p75(NTR)-selective nerve growth factor mutant (Delta9/13 NGF) were utilized to selectively stimulate TrkA or p75(NTR) signaling, respectively. The contribution of individual and combined receptor effects was analyzed in terms of downstream signaling and certain end points. The results suggest two unique functions for the high affinity heteromeric NGF receptor site: ( a) integration of both the MAPK and Akt pathways in the production of NGF-induced neurite outgrowth, and (b) rapid and sustained activation of the Akt pathway, with consequent long term cellular survival. Whereas activation of TrkA signaling is sufficient for eliciting neurite outgrowth in PC12 cells, signaling through p75(NTR) plays a modulatory role, especially in the increased formation of fine, synaptic "bouton-like" structures, in which both TrkA and p75(NTR) appear to co-localize. In addition, a new interaction in the TrkA/p75(NTR) heteromeric receptor signal transduction network was revealed, namely that NGF-induced activation of the MAPK pathway appears to inhibit the parallel NGF-induced Akt pathway.