Functional cooperation between TrkA and p75(NTR) accelerates neuronal differentiation by increased transcription of GAP-43 and p21(CIP/WAF) genes via ERK1/2 and AP-1 activities.
The biological complexity of NGF action is achieved by binding two distinct neurotrophin receptors, TrkA and p75(NTR). While several reports have provided lines of evidence on the interaction between TrkA and p75(NTR) 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 p75(NTR) may affect TrkA downstream signaling with respect to neuronal differentiation. Here, we have shown that cooperation between p75(NTR) 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.
Diolaiti
Daniel
D
Department of Biology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.
Bernardoni
Roberto
R
Trazzi
Stefania
S
Papa
Antonella
A
Porro
Antonio
A
Bono
Françoise
F
Herbert
Jean-Marc
JM
Perini
Giovanni
G
Della Valle
Giuliano
G
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D010766:Phosphorylation; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D050759:Cyclin-Dependent Kinase Inhibitor p21; D019922:GAP-43 Protein; D020800:Receptor, Nerve Growth Factor; D018808:Transcription Factor AP-1; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3