The biological complexity of NGF action is achieved by binding two distinct Neurotrophin
receptors, TrkA and p75NTR. While several reports have provided lines of evidence on the
interaction between TrkA and p75NTR at the plasma membrane, much fewer data are
available on the consequence of such an interaction in terms of intracellular signaling. In
this study, we have focused on how p75NTR may affect TrkA downstream signaling with
respect to neuronal differentiation. Here, we have shown that cooperation between p75NTR
and TrkA results in an increased NGF-mediated TrkA autophosphorylation, leads to a
sustained activation of ERK1/2 and accelerates neurite outgrowth. Interestingly, neurite
outgrowth is concomitant with a selective enhancement of the AP-1 activity and the
transcriptional activation of genes such as GAP-43 and p21(CIP/WAF), known to be
involved in the differentiation process. Collectively, our results unveil a functional link
between the specific expression profile of neurotrophin receptors in neuronal cells and the
NGF-mediated regulation of the differentiation process possibly through a persistent ERKs
activation and the selective control of the AP-1 activity. In our studies we discuss the
functional role of the neurotrophin receptor p75NTR and TrkA in a ligand-dependent signal
transduction.
It is known that p75NTR is also involved in the mediation of cell death ligand dependent.
Here we show for the first time that the membrane receptor p75NTR, upon binding to b-
Amyloid (Ab) peptide, is able to transduce a cytotoxic signal through a mechanism very
similar to the one adopted by Tumor Necrosis Factor Receptor 1 (TNFR1), when activated
by TNFa. We define that in neuroblastoma cell line Ab cytotoxicity signals through a
pathway depending on p75NTR death domain (DD), mostly through some specific
conserved residues. We identified that TRADD is the first interactor recruiting to the
membrane and activates JNK and NF-kB transcription factors. Since Ab is defined as the
most important aetiologic element associated with the Alzheimer’s Disease (AD),
characterization of the mechanism involved in the mediation of the neurodegeneration can
suggest also new therapeutic approaches.
| Identifer | oai:union.ndltd.org:unibo.it/oai:amsdottorato.cib.unibo.it:679 |
| Date | 03 April 2008 |
| Creators | Papa, Antonella <1978> |
| Contributors | Della Valle, Giuliano |
| Publisher | Alma Mater Studiorum - Università di Bologna |
| Source Sets | Università di Bologna |
| Language | English |
| Detected Language | English |
| Type | Doctoral Thesis, PeerReviewed |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
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