Abstract:
Autophagy is a not well-understood conserved mechanism activated during
nutritional deprivation in order to maintain cellular homeostasis. In the present
study, we investigated the correlations between autophagy, apoptosis and the MAPK
pathways in melanoma cell lines. We demonstrated that during starvation the EGF
receptor mediated signaling activates many proteins involved in the MAPK pathway.
Our data also suggest a previously unidentified link between the EGFR and Beclin-1
in melanoma cell line. We demonstrated that, following starvation, EGFR binds
and tyrosine-phosphorylates Beclin-1, suggesting that it may play a key inhibitory
role in the early stage of starvation, possibly through the Beclin-1 sequestration.
Furthermore, EGFR releases Beclin-1 and allows initiating steps of the autophagic
process. Interestingly enough, when the EGFR pathway was blocked by anti-EGF
antibodies, immunoprecipitated Beclin-1 did not bind the phospho-EGFR. In addition,
an extended binding of p-Bcl2 either with Beclin-1 or with Bax was observed with a
decreased activation of the stress-induced JNK kinase, thus avoiding the transduction
pathways that activate autophagy and apoptosis, respectively. For this reason, we
advance the hypothesis that the activation of the EGFR is a necessary event that
allows the ignition and progression of the autophagic process, at least in melanoma
cells.
