CONICET | Buscador de Institutos y Recursos Humanos

Background: Histamine, through histamine H2 receptor (H2R), modulates different biological processes, involvingthe modulation of PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways. Many evidences have demonstratedthe existence and importance of the crossregulation between these two signaling pathways. The aim of thepresent work was to determine the molecular mechanisms leading to PI3K and ERK pathways modulation inducedby the H2R agonist amthamine and to evaluate the possible interplay between them.Methods: Phosphorylation levels of ERK and Akt were examined by Western blot in HEK293T cells expressing thehuman H2R, in the presence of H2R agonist and dominant negative mutants or pharmacological inhibitors of differentproteins/pathways. Transcriptional activity assays were assessed to determine SRE activity. Amthaminemediatedcellular proliferation was investigated in MA-10A cells in the presence of PI3K inhibitor.Results: H2R agonist inhibits PI3K/Akt/mTOR and stimulates Ras/MEK/ERK pathways. Moreover, PI3K/Akt/mTORsignaling inhibition is necessary to achieve H2R mediated ERK activation. In the presence of a constitutive activemutant of Akt, amthamine is not able to mediate ERK activation. This crosstalk affects classical ERK downstreamtargets such as Elk1 phosphorylation and the transcriptional activity of the SRE, classically associated to proliferation.We further demonstrate that amthamine-induced proliferation in Leydig MA-10 tumor cells, is enhancedby LY294002, a PI3K inhibitor.Conclusions: These results describe a crosstalk between PI3K/AKT/mTOR and Ras/MEK/ERK pathways induced byH2R stimulation with implications in cell proliferation.General significance: This work indicates that the modulation of PI3K/AKT/mTOR pathway by H2R in turn regulatesRas/MEK/ERK activation conditioning the proliferative capacity of the cells