Antifolate/folate-activated HGF/c-Met signalling pathways in mouse kidneys-the putative role of their downstream effectors in cross-talk with androgen receptor

This in vivo study of mouse kidneys was focused on the identification of protein mediators involved in the cross-talk between two signalling pathways. One pathway was triggered by testosterone via an androgen receptor, AR, and the other induced by CB 3717/folate via HGF, and its membrane receptor c-Met. Sequential activation of these pathways leads to a drastic decrease of testosterone-induced ornithine decarboxylase, ODC, expression. We proved that CB 3717/folate-induced ODC expression is Akt-dependent. CB 3717/folate activates Akt and ERK1/2 kinases, PTEN phosphatase and also up-regulates cyclin D2 and PCNA, but decreases GSK3β and cyclin D1 protein levels. Testosterone activation of AR induces GSK3β and PTEN. Results of the sequential activation of the studied signalling pathways suggest that Akt, GSK3β and possibly ERK1/2 kinases may participate in the negative cross-talk and attenuation of AR transactivity, while the involvement of PTEN and cyclin D1 seems to be doubtful.